Origin and Evolution of the Self-Organizing Cytoskeleton...

Origin and Evolution of the Self-OrganizingCytoskeleton in the Network of EukaryoticOrganelles

Gaspar Jekely

Max Planck Institute for Developmental Biology, 72076 Tuebingen, Germany

Correspondence: [email protected]

The eukaryotic cytoskeleton evolved from prokaryotic cytomotive filaments. Prokaryoticfilament systems show bewildering structural and dynamic complexity and, in manyaspects, prefigure the self-organizing properties of the eukaryotic cytoskeleton. Here, thedynamic properties of the prokaryotic and eukaryotic cytoskeleton are compared, and howthese relate to function and evolution of organellar networks is discussed. The evolution ofnew aspects of filament dynamics in eukaryotes, including severing and branching, and theadvent of molecular motors converted the eukaryotic cytoskeleton into a self-organizing“active gel,” the dynamics of which can only be described with computational models.Advances in modeling and comparative genomics hold promise of a better understandingof the evolution of the self-organizing cytoskeleton in early eukaryotes, and its role in theevolution of novel eukaryotic functions, such as amoeboid motility, mitosis, and ciliaryswimming.

The eukaryotic cytoskeleton organizes spaceon the cellular scale and this organization

influences almost every process in the cell. Or-ganization depends on the mechanochemicalproperties of the cytoskeleton that dynamicallymaintain cell shape, position organelles, andmacromolecules by trafficking, and drive loco-motion via actin-rich cellular protrusions, cil-iary beating, or ciliary gliding. The eukaryoticcytoskeleton is best described as an “active gel,”a cross-linked network of polymers (gel) inwhich many of the links are active motors thatcan move the polymers relative to each other(Karsenti et al. 2006). Because prokaryoteshave only cytoskeletal polymers but lack motorproteins, this “active gel” property clearly sets

the eukaryotic cytoskeleton apart from pro-karyotic filament systems.

Prokaryotes contain elaborate systems ofseveral cytomotive filaments (Lowe and Amos2009) that share many structural and dynamicfeatures with eukaryotic actin filaments andmicrotubules (Lowe and Amos 1998; van denEnt et al. 2001). Prokaryotic cytoskeletal fila-ments may trace back to the first cells and mayhave originated as higher-order assemblies ofenzymes (Noree et al. 2010; Barry and Gitai2011). These cytomotive filaments are requiredfor the segregation of low copy number plas-mids, cell rigidity and cell-wall synthesis, celldivision, and occasionally the organization ofmembranous organelles (Komeili et al. 2006;

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Thanbichler and Shapiro 2008; Lowe and Amos2009). These functions are performed by dy-namic filament-forming systems that harnessthe energy from nucleotide hydrolysis to gen-erate forces either via bending or polymeriza-tion (Lowe and Amos 2009; Pilhofer and Jensen2013). Although the identification of actin andtubulin homologs in prokaryotes is a majorbreakthrough, we are far from understandingthe origin of the structural and dynamic com-plexity of the eukaryotic cytoskeleton.

Advances in genome sequencing and com-parative genomics now allow a detailed re-construction of the cytoskeletal componentspresent in the last common ancestor of eukary-otes. These studies all point to an ancestrallycomplex cytoskeleton, with several families ofmotors (Wickstead and Gull 2007; Wicksteadet al. 2010) and filament-associated proteinsand other regulators in place (Jekely 2003; Ri-chards and Cavalier-Smith 2005; Rivero andCvrckova 2007; Chalkia et al. 2008; Eme et al.2009; Fritz-Laylin et al. 2010; Eckert et al. 2011;Hammesfahr and Kollmar 2012). Genomic re-constructions and comparative cell biology ofsingle-celled eukaryotes (Raikov 1994; Cava-lier-Smith 2013) allow us to infer the cellularfeatures of the ancestral eukaryote. These an-alyses indicate that amoeboid motility (Fritz-Laylin et al. 2010; although, see Cavalier-Smith2013), cilia (Cavalier-Smith 2002; Mitchell2004; Jekely and Arendt 2006; Satir et al. 2008),centrioles (Carvalho-Santos et al. 2010), phago-cytosis (Cavalier-Smith 2002; Jekely 2007; Yutinet al. 2009), a midbody during cell division(Eme et al. 2009), mitosis (Raikov 1994), andmeiosis (Ramesh et al. 2005) were all ancestraleukaryotic cellular features. The availability offunctional information from organisms otherthan animals and yeasts (e.g., Chlamydomonas,Tetrahymena, Trypanosoma) also allow more re-liable inferences about the ancestral functionsof cytoskeletal components (i.e., not only theirancestral presence or absence) and their regu-lation (Demonchy et al. 2009; Lechtreck et al.2009; Suryavanshi et al. 2010).

The ancestral complexity of the cytoskele-ton in eukaryotes leaves a huge gap betweenprokaryotes and the earliest eukaryote we can

reconstruct (provided that our rooting of thetree is correct) (Cavalier-Smith 2013). Never-theless, we can attempt to infer the series ofevents that happened along the stem lineage,leading to the last common ancestor of eukary-otes. Meaningful answers will require the useof a combination of gene family history recon-structions (Wickstead and Gull 2007; Wicksteadet al. 2010), transition analyses (Cavalier-Smith2002), and computer simulations relevant tocell evolution (Jekely 2008).

OVERVIEW OF CYTOSKELETAL FUNCTIONSIN PROKARYOTES AND EUKARYOTES

In the first section, an overview of the functionsand components of the cytoskeleton in pro-karyotes and eukaryotes is provided. To obtaina general overview, cellular structures (e.g., cellwall, kinetochore) and cytoskeletal proteins ofprokaryotes and eukaryotes are represented asnetworks (Figs. 1 and 2). In the networks, thenodes represent proteins or cellular structuresand the edges represent the co-occurrence ofterms in PubMed entries, used as a proxy forfunctional connections. The nodes are clusteredbased on an attractive force (Frickey and Lupas2004) calculated as the number of entries inwhich the two terms co-occur divided by thenumber of entries in which the less frequentterm occurs.

For prokaryotes, all filament types are rep-resented in one map, although many of theseare specific to certain taxa and do not coexistin the same cell (Fig. 1A). For eukaryotes, thebudding yeast (Saccharomyces cerevisiae) cyto-skeletal network (Fig. 1B) and a simplified hu-man cytoskeletal network is depicted (Fig. 2)(eukaryotic cytoskeletal proteins were retrievedfrom UniProt database [www.uniprot.org] us-ing the GO ID GO:0005856).

The prokaryotic network has three majormodules, the plasmid partitioning systems, thecell division machinery (divisome) using theFtsZ contractile ring, and the MreB filamentsystem involved in cell-wall synthesis and scaf-folding.

Components of the first prokaryotic cyto-skeletal module function in the positioning of

G. Jekely

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DNA within the cell, driven by forces generatedeither by the polymerization or the depolyme-rization of filaments. These widespread and di-verse filament systems are either responsible forthe segregation of low copy number plasmids,

or chromosome segregation (Pilhofer and Jen-sen 2013). DNA partitioning systems generallyconsist of a centromere-like region on DNA, aDNA-binding adaptor protein, and a filament-forming NTPase that polymerizes in a nucleo-

Figure 1. Prokaryotic and yeast cytoskeletal-organellar network. Cytoskeletal-organellar network of (A) pro-karyotes, and (B) yeast. The nodes correspond to gene names or cytological terms.

Origin and Evolution of the Cytoskeleton

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tide-dependent manner. Three types of filamentsystems have been described in prokaryotes.Type I systems use Walker ATPases (ParA-like),type II systems have actin-like ATPases (ParM-like), and type III systems have tubulin-likeGTPases (TubZ-like).

The second widespread prokaryotic fila-ment system functions in cell division. Cell di-vision in all eubacteria and most archaebacteriarelies on FtsZ-mediated binary fission. The tu-bulin-like GTPase, FtsZ (Lowe and Amos 1998),forms filaments that organize into a contractilering (“Z-ring”) at the cell center and triggerfission. The Z-ring is thought to be attachedto the membrane at the division site by an “A-ring,” formed by the actin-like filament-form-ing protein, FtsA (Szwedziak et al. 2012). GTP-

dependent FtsZ-filament bending may initiatemembrane constriction (Osawa et al. 2009).The Z-ring also recruits several downstreamcomponents (e.g., FtsI, FtsW) that contributeto the remodeling of the peptidoglycan cell wallduring septation (Lutkenhaus et al. 2012). Inarchaebacteria that lack a peptidoglycan walland FtsA (bar one exception), cell division pro-ceeds using a distinct, poorly understood ma-chinery (Makarova et al. 2010).

The third prokaryotic filament system usesMreB, a homolog of actin that can form fila-ments in an ATP- or GTP-dependent manner(van den Ent et al. 2001). MreB is found in non-spherical bacteria and is involved in cell-shapemaintenance by localizing cell-wall synthesisenzymes. MreB is linked to the peptidoglycan

Figure 2. Human cytoskeletal-organellar network. The nodes correspond to gene names or cytological terms.

G. Jekely




precursor synthesis complex (Mur proteins andMraY) and the peptidoglycan assembly com-plex (PBPs and lytic enzymes, e.g., MltA). Lossof MreB leads to the growth of large, malformedcells that show membrane invaginations (Ben-dezu and de Boer 2008). In vitro MreB formsfilament bundles and sheets (Popp et al. 2010c),whereas in vivo MreB filaments form patchesunder the inner membrane that move togetherwith the cell-wall synthesis machinery, proba-bly driven by peptidoglycan synthesis (Do-mınguez-Escobar et al. 2011; Garner et al.2011). MreB filament patches also contributeto the mechanical rigidity of the cell, indepen-dent of their function in cell-wall synthesis(Wang et al. 2010).

The eukaryotic cytoskeletal networks (rep-resented by yeast and human) include a cell-division module including the spindle, centro-mere, and centrosome (spindle pole body, SPBin yeast). This module functions in chromo-some segregation, during which kinetochoresmust interact with spindle microtubules. Prop-er attachment is, for example, facilitated byStu2 (ortholog of vertebrate XMAP215), a pro-tein that is transferred to shrinking microtubuleplus ends when they reach a kinetochore andstabilizes them (Gandhi et al. 2011). Other ex-amples from this module are Aurora kinase andINCENP (yeast Ipl1 and Sli15), proteins thatensure that sister kinetochores attach to micro-tubules from opposite spindle poles during mi-tosis (Tanaka et al. 2002).

Another important subnetwork in the yeastcytoskeleton is involved in bud-site selectionand the formation of a contractile actomyosinring. An example in this network is yeast Myo1,a two-headed myosin-II that localizes to thedivision site and promotes the assembly of acontractile actomyosin ring and septum forma-tion (Fang et al. 2010). The membrane traffick-ing subnetwork includes regulators of vesicletrafficking and cargo sorting, including the yeastdynamin-like GTPase, Vps1. Vps1 is involved invacuolar, Golgi, and endocytic trafficking (Vateret al. 1992).

The human cytoskeletal network includesseveral other modules absent from yeast. Theseinclude a module centered around the cilium,

and one module for the formation of lamel-lipodia, filopodia, and phagocytosis. The for-mer includes ciliary transport (intraflagellartransport, BBSome), structural, and signaling(PKD2) proteins; the latter includes proteinsthat reorganize cortical actin filaments, includ-ing the Arp2/3 complex (ACTR2/3) (Mullinset al. 1998) and the Cdc42 effector N-WASP,an activator of the Arp2/3 complex (Takenawaand Miki 2001). The human network also con-tains several animal-specific modules, includ-ing modules related to stereocilia of inner-earhair cells, muscle, neurons (dendrite, synapse),skin, and structures mediating cell–cell adhe-sion (desmosome).

Despite the vastly different organizationand complexity of the eukaryotic and prokary-otic cytoskeletal networks, we know that thereis evolutionary continuity between them. Theeukaryotic cytoskeletal networks are centeredaround actin filaments and microtubules thatevolved from homologous filament systems inprokaryotes (Lowe and Amos 1998; van den Entet al. 2001).

PROKARYOTIC ORIGIN OF THE MAJORCOMPONENTS OF THE EUKARYOTICCYTOSKELETON

In this section, an overview of the diversity ofactin- and tubulin-like filament-forming pro-teins is given, and a few other key cytoskeletalcomponents are discussed, for which distantprokaryotic homologs could be identified.

Besides actin- and tubulin-like filaments,prokaryotes also contain filament-formingWalker ATPases (ParA and SopA), with no poly-mer-forming homologs in eukaryotes. The evo-lution of this family will not be discussed.

Origin of Eukaryotic Actin Filaments

Actin is a member of the sugar kinase/HSP70/actin superfamily (Bork et al. 1992). This familyalso includes different prokaryotic filament-forming proteins, including MreB, FtsA, theplasmid-partitioning protein ParM and its rel-atives, and an actin family specific to archaebac-teria (crenactins).





To represent the diversity of actin-like pro-teins and their phyletic distribution in a globalmap, I clustered a large dataset of actin-like se-quences based on pairwise BLASTP P valuesusing force-field-based clustering (Fig. 3A–C)(Frickey and Lupas 2004). Clustering can be veryefficient if large numbers of sequences needto be analyzed. Given that, at least in prokary-otes, there is a tight link between orthologsand bidirectional best BLAST hits (Wolf andKoonin 2012). BLAST-based clustering can ef-ficiently recover orthology groups in large datasets. Although clustering methods still lack so-phisticated analysis tools that are common inalignment-based molecular phylogeny methods(e.g., rate heterogeneity among sites), the resultsfrom similarity-based clustering can agree wellwith molecular phylogeny (Jekely 2013; Mira-beau and Joly 2013). Cluster maps can also pro-vide a general overview of taxonomic distribu-

tion and sequence similarity, parameters thatare not easily inferred from phylogenetic trees.Clustering is best thought of as a representationof sequence data as a similarity network, al-lowing evolutionary biologists to draw inferenc-es about sequence evolution that are comple-mentary to answers based on phylogeny (for athoughtful introduction to the use of similaritynetworks, see Halary et al. 2013).

The actin similarity network revealed all ac-tin-like protein families and their phyletic dis-tribution. Filamentous actin was at the centerof the cluster of eukaryotic actins and the di-verse Arp families radiated from this center. The“centroid” position of actin (Fritz-Laylin et al.2010) suggests that it represents the most ances-tral eukaryotic sequence, and therefore maxi-mizes all the blast hits to other eukaryotic actins.The ancestral nature of actin is also in agree-ment with its role in filament formation, where-

Figure 3. Cluster analysis of actin- and tubulin-like proteins. Sequence-similarity-based clustering was per-formed on (A-C) prokaryotic and eukaryotic actin-like proteins, and (D-F) prokaryotic and eukaryotic tubulin-like proteins. In both cases, an exhaustive, 90% nonredundant set of Uniprot is shown. The clusters were coloredto reflect domain-wide (A, D), or eukaryote-wide (C, F) phyletic distribution. The BLASTP connections of (B)crenactins, and (E) artubulins were shown, with hits of different P-value cutoffs shown in different hues of red.

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as the more derived Arps are either regulators offilament branching and nucleation (the Arp2/3complex) (Mullins et al. 1998), or have unrelat-ed functions.

The similarity map also reveals the prokary-otic MreB, MamK, ParM, and crenactin fami-lies (the more derived FtsA was excluded) asdistinct clusters. Among the prokaryotic actins,crenactins show the most similarity to eukary-otic actins and have been proposed to be thedirect ancestors of eukaryotic actins (Yutin etal. 2009; Bernander et al. 2011). Crenactin wasshown to form helical structures in Pyrobaculumcells, and is only found in rod-shaped archae-bacteria (Ettema et al. 2011), indicating thatit may regulate cell shape. Crenactins share twounique inserts with eukaryotic actins and otherinserts that are uniquely shared with the actin-like protein Arp3 (Yutin et al. 2009). This is apuzzling observation and either suggests thatArp3 (arguably, a derived regulatory actin) rep-resents the ancestral state, or crenactins origi-nated via horizontal gene transfer (HGT) fromeukaryotes to archaebacteria. The phylogenet-ic trees showing a sister relationship of crenac-tins to all eukaryotic actins (Yutin et al. 2009;Bernander et al. 2011) should be interpretedwith caution, given that these trees have long in-ternal branches, use very distant outgroups, andhave few aligned positions. If crenactins werederived Arp3 proteins, they would also be ex-pected to branch artificially at a deeper node,not as a sister to Arp3, because of long-branchattraction. Future structural studies of crenac-tins may be able to clarify the history of crenac-tins, relative to eukaryotic actins.

Origin of Microtubules

Microtubules are dynamic polymer tubesformed by 13 laterally interacting protofila-ments of a/b-tubulin heterodimers. Like actinfilaments, microtubules are universal in eukary-otes. Besides the canonical a/b-tubulins, sever-al other tubulin forms have ancestrally beenpresent in eukaryotes, including d, g, and 1-tu-bulins. The prokaryotic homologs of tubulinsinclude FtsZ, TubA, BtubA/BtubB from Verru-comicrobia, and artubulins, so far only found

in the archaebacterium Nitrosoarchaeum (Yutinand Koonin 2012).

The cluster map of tubulins provides anoverview of the phyletic distribution of all fam-ilies (Fig. 3D–F). a, b, g, d, and 1-tubulins areall ancestrally present in eukaryotes, given theirbroad distribution and their presence in exca-vates, a protist group that potentially representsa divergence close to the root of the eukaryotictree (Cavalier-Smith 2013). 1 and d-tubulin areonly present in lineages with a cilium.

There are two independent, phyletically re-stricted groups of prokaryotic tubulins withhigher sequence similarity to eukaryotic tubu-lins than FtsZ, BtubA/BtubB from Prostheco-bacter, and the archaebacterial artubulins.

BtubA and BtubB were identified in Pros-thecobacter (Jenkins et al. 2002), belongingto the Verrucomicrobia. These proteins showhigh-sequence (approximately 35% identity)and structural similarity to eukaryotic a/b-tu-bulins, and form tubulin-like protofilamentsmade up of BtubA/BtubB heterodimers (Schlie-per et al. 2005). Despite the close similarityto a/b-tubulins, there is no one-to-one corre-spondence between the a/b and BtubA/BtubBheterodimers. Instead, both BtubA and BtubBshow structural features that are specific to ei-thera or b-tubulin (Schlieper et al. 2005). This,together with the equal distance from a/b-tu-bulin in sequence space (Fig. 3F), suggests thatBtubA/BtubB represent a state in tubulin evo-lution preceding the duplication of a/b-tubu-lins in stem eukaryotes. Because a/b-tubulinsare the structural components of microtubules,their origin by gene duplication was probablythe first event in the history of eukaryotic tubu-lin duplications. The close similarity of BtubA/BtubB to eukaryotic tubulins suggests that theyoriginated by HGT from eukaryotes to Prosthe-cobacter (Schlieper et al. 2005).

Nevertheless, the ancestral character ofBtubA/BtubB, uniting features of a/b-tubulinsuggests that BtubA/BtubB originated by anancient HGT event, and these tubulins mayprovide insights into the early evolution of mi-crotubules. Interestingly, and in contrast to allother prokaryotic tubulins, BtubA/BtubB canform tubules formed by five protofilaments (in-





steadof13as ineukaryotes) (Pilhoferetal.2011).These simpler, smaller tubules may represent anintermediate stage in the evolution of the eu-karyotic tubulin skeleton. The ability to formmicrotubules may also explain the higher se-quence conservation of BtubA/BtubB, despitetheir potential early origin.

Another class of prokaryotic tubulins, ar-tubulin, has recently been identified in Nitro-soarchaeum and has been proposed to be theancestor of eukaryotic tubulins (Yutin and Ko-onin 2012). Artubulins show higher sequencesimilarity to eukaryotic tubulins than to FtsZ.In a phylogenetic tree, artubulins branched as asister to all eukaryotic tubulins. In the clustermap, artubulins appear at the periphery of theeukaryotic tubulins (Fig. 3D), and show verylow-sequence similarity to FtsZ. Coloring thenodes connected to artubulins according totheir similarity (BLASTP value) to artubulinsindicates that g-tubulins are closest in sequencespace. g-Tubulin regulates microtubule nucle-ation and it is more likely that it represents aderived tubulin class, not one ancestral to a/b-tubulins. These considerations, together withthe very limited taxonomic distribution of ar-tubulins cast further doubt on their ancestralstatus. The clustering results are consistent withartubulins representing a derived g-tubulin, ac-quired by HGT from eukaryotes to Nitroso-archaeum. The original molecular phylogenymay have grouped artubulins deep because ofa long-branch artifact caused both by the de-rived nature of artubulins and the very distantoutgroup. Structural analysis and polymeriza-tion assays of artubulins will help to better eval-uate these alternative scenarios.

Overall, the origin of eukaryotic tubulinfrom either BtubA/BtubB or artubulins is notconvincingly shown and both may have beenacquired by HGT from eukaryotes. If this is thecase, then the most likely ancestor of eukaryotictubulins remains to be FtsZ.

Origin of Molecular Motors

Molecular motors are mechanochemical en-zymes that use ATP hydrolysis to drive a me-chanical cycle (Vale and Milligan 2000). Motors

step either along microtubules (kinesins anddyneins) or the actin cytoskeleton (myosins)and are linked to and move cargo (moleculesor organelles) around the cell. Several familiesof all three motor types are ancestrally present ineukaryotes (Richards and Cavalier-Smith 2005;Wickstead and Gull 2007; 2011; Wickstead et al.2010).

The origin of motors is unknown becauseno direct prokaryotic ancestor has been identi-fied. However, kinesins and myosins have com-mon ancestry and share a catalytic core and a“relay helix” that transmits the conformationalchange in the catalytic core to the polymer bind-ing sites and the mechanical elements (Kullet al. 1996). These motors are distantly relatedto and evolved from GTPase switches (Leipe etal. 2002), molecules that likewise undergo con-formational changes on nucleotide binding andhydrolysis (Vale and Milligan 2000).

Other Prokaryotic Homologsof Cytoskeletal Proteins

The prokaryotic ancestry of cytoskeletal com-ponents other than actin and tubulin can alsobe ascertained by sensitive sequence and struc-tural comparisons.

Profilin is a protein that breaks actin fil-aments (Schutt et al. 1993). Profile–profilesearches with profilin using HHpred recoveredthe bacterial gliding protein MglB (Probab ¼95.44, E value ¼ 0.73) and other proteins withthe related Roadblock/LC7 domain. Profilinand MglB also show structural similarity, asshown by PDBeFold searches (profilin 3d9y:Band MglB 3t1q:B with an RMSD of 2.65). Thesequence- and structure-based similarities es-tablish profilin as a homolog of the Roadblockfamily. In eukaryotes, members of this familyare associated with ciliary and cytoplasmic dy-nein, and in prokaryotes, MglB is a GTPase ac-tivating protein of the gliding protein, the Ras-like GTPase MglA (Leonardy et al. 2010).

The microtubule-severing factors kataninand spastin, members of the AAAþATPase fam-ily, also have prokaryotic origin. AAAþ ATPaseshave several ancient families with broad phyleticdistribution, and the katanin family is a mem-

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ber of the classical AAA clade (Iyer et al. 2004).This clade includes bacterial FtsH (an AAAþ

ATPase with a carboxy-terminal metallopro-tease domain), a protein that is localized to theseptum in dividing Bacillus subtilis cells (Wehrlet al. 2000), in which it may degrade FtsZ (Anil-kumar et al. 2001). Whether the katanin familyof microtubule-severing factors evolved by themodification of FtsH is not resolved.

A third cytoskeletal regulator with pro-karyotic ancestry is the enzyme a-tubulin N-acetyltransferase (mec-17) that stabilizes mi-crotubules in cilia and neurites by a-tubulinacetylation. The phyletic distribution of thisenzyme tightly parallels that of cilia. a-TubulinN-acetyltransferase is a member of the Gcn5-re-

lated N-acetyltransferase superfamily (Steczkie-wicz et al. 2006; Taschneret al. 2012), widespreadin prokaryotes (Neuwald and Landsman 1997).

DYNAMIC PROPERTIES OF THEPROKARYOTIC AND EUKARYOTICCYTOSKELETON

In the following section, the dynamic proper-ties of the prokaryotic and eukaryotic cytoskel-eton are compared. Prokaryotic filament-form-ing systems show remarkable properties that,in many respects, prefigure the dynamic, self-organized properties of the eukaryotic cyto-skeleton (Fig. 4). The dynamic features of pro-karyotic filaments include filament nucleation

Dimericnucleus

A G

H

I

J

K

B

C

D

E

F

Growthcatastropherescue

Steady growth

Growth

Membrane

Shrinkage

Severing factors

Centrosome

Microtubules

Arp2/3 Tpx2, γ-TuRC

Actinfilaments

Stabilized filament

Figure 4. Dynamic properties of the cytoskeleton. Dynamic properties and self-organized patterns of theprokaryotic (A-F), and eukaryotic (G-K) cytoskeleton. (A) Filament nucleation by a dimeric nucleus, (B)dynamic instability, (C) filament capping, (D) treadmilling, (E) bipolar growth of antiparallel filaments, and(F) higher-order structures, such as filament pairs, asters, meshes, sheets. Eukaryotes, in addition, display (G)filament branching, (H ) dynamic overlap of antiparallel filaments, (I) spindle and asters, (J ) filament severing,and (K) actin networks, axoneme, and basal bodies.





(Lim et al. 2005), polymerization and depoly-merization, dynamic instability (Garner 2004),treadmilling (Larsen et al. 2007), directional po-larization with plus and minus ends (Larsenet al. 2007), the formation of higher-order struc-tures (Szwedziak et al. 2012), and force genera-tion by filament growth, shrinkage, or bending.These features enable prokaryotic filaments toperform various functions such as the position-ing of membranous organelles, chromosomeand plasmid segregation, cell-shape changes,cell division, and contribution to the mechani-cal integrity of the cell (Wang et al. 2010).

The eukaryotic cytoskeleton shares all of theabove features with the cytomotive filamentsof prokaryotes (Fig. 4), but evolved addition-al features (Table 1). First, the dynamic proper-ties shared between prokaryotes and eukaryotesare discussed. Then, an overview is given of theunique properties of the eukaryotic cytoskel-eton that represent evolutionary innovationsduring the origin of eukaryotes.

Filament Nucleation, Polymerization,Depolymerization, and Capping

The regulation of the polymerization and de-polymerization of polymers is essential for theproper functioning of filament systems. Fila-ment growth can be influenced by various fac-tors, including monomer concentration, nucle-otides, and accessory factors, such as nucleatingor polymerizing proteins. In eukaryotes, thespontaneous nucleation of microtubules andactin filaments is slow. Filament nucleationtherefore represents an important regulatorycomponent, allowing the positioning of grow-ing filaments in the cell (Goley and Welch2006; Kollman et al. 2011). In contrast, pro-karyotic filaments commonly assemble rapidlyand spontaneously, although nucleation may,in some cases, facilitate assembly. For example,FtsZ filament assembly proceeds via an FtsZdimer that can serve as a nucleus for polymeri-zation (Chen et al. 2005).

Cytoskeletal filament dynamics is also reg-ulated by filament capping. Capping includesthe binding of factors to the end of a filament,thereby preventing disassembly. Eukaryotic ac-

tin fibers and microtubules are both regulatedby capping (Cooper and Schafer 2000; Jiang andAkhmanova 2011). In prokaryotic DNA parti-tioning systems, filament assembly is common-ly facilitated by the centromere-adaptor proteincomplex that stabilizes the growing end of thefilament. This has been observed for all threetypes of prokaryotic filaments (Table 1) (Limet al. 2005; Aylett et al. 2010; Kalliomaa-Sanfordet al. 2012; Popp et al. 2012). Capping by theDNA-adaptor complex ensures the steady poly-merization of the filaments by the incorpora-tion of new subunits, thereby moving the plas-mid or the chromosome (Salje and Lowe 2008;Kalliomaa-Sanford et al. 2012).

Treadmilling

Treadmilling is an important feature of eu-karyotic actin (Wegner 1976) and microtubules(Shaw 2003), and is characterized by filamentpolymerization at one end and depolymeriza-tion at the other end. This results in the appar-ent motion of the filament, although the indi-vidual subunits stay in place. Treadmilling hasalso been observed in the actin-like and tubulin-like DNA segregation proteins (Table 1) (Kimet al. 2006; Larsen et al. 2007; Derman et al.2009; Popp et al. 2010b, 2010c). Treadmillingof the tubulin-like protein TubZ was shown tobe important for plasmid stability. TubZ with amutation in a catalytic residue forms stable fil-aments that are unable to undergo treadmilling.The introduction of this mutant into the cellleads to the loss of the associated plasmid, high-lighting the importance of filament dynamicsfor proper plasmid segregation (Larsen et al.2007).

Dynamic Instability

Cytoskeletal filaments often show dynamic in-stability, characterized by the alternation ofsteady polymerization and catastrophic shrink-age. This behavior is also characteristic of eu-karyotic microtubules (Mitchison and Kirsch-ner 1984). Microtubules are polar, growing attheir plus ends by the addition of tubulin het-erodimers. Tubulins use GTP for filament as-

G. Jekely




sembly, and GTP hydrolysis within the mi-crotubule generates tension that is required fordynamic instability (Karsenti et al. 2006). Dy-namic instability represents an efficient strategyto search in space (Holy and Leibler 1994). Dy-namic instability is important for proper DNAcapture and positioning in both prokaryotesand eukaryotes. The actin-like proteins ParM(Garner 2004) and Alp7 (Derman et al. 2009)were observed to undergo dynamic instabilityin vivo. The nucleotide-bound monomers forma cap that stabilizes the filament (Garner 2004),but on nucleotide hydrolysis, the filament rap-idly disassembles. ParM filaments are polar, but

when two filaments associate in an antiparallelfashion, they polarize bidirectionally (Gayathriet al. 2012). The filaments are dynamic andsearch the cell. Binding of the ParR/parC adap-tor/centromere complex to the ends of ParMfilaments inhibits dynamic instability, and pro-motes filament growth. This “search and cap-ture” mechanism allows efficient plasmid seg-regation by pushing plasmids apart in a bipolarspindle.

The Walker ATPase SopA also forms dy-namic filaments, the dynamics of which areimportant for plasmid segregation because mu-tants that form static polymers inhibit segre-

Table 1. Overview of the dynamic properties of prokaryotic and eukaryotic filament systems

Prokaryotic actin-

like filaments

Prokaryotic

tubulin-like

filaments

Prokaryotic

Walker-ATPase

filaments

Eukaryotic actin

filaments

Eukaryotic

microtubules

Capping ParM (Popp et al.2012)

TubZ (Aylettet al. 2010)

SopA (Lim et al.2005), SegA(Kalliomaa-Sanford et al.2012)

Cooper andSchafer 2000

Jiang andAkhmanova2011

Treadmilling AlfA (Popp et al.2010b), MreB (Kimet al. 2006; Poppet al. 2010c), Alp7A(Derman et al.2009)

TubZ (Larsenet al. 2007)

Wegner 1976 Shaw 2003

Dynamicinstability

ParM (Garner 2004),Alp7 (Derman et al.2009; Drew andPogliano 2011)

SopA (Lim et al.2005)

Mitchison andKirschner1984

Higher-orderstructures

ParM (Garner et al.2007; Gayathri et al.2012), MreB (Poppet al. 2010c), FtsA(Popp et al. 2010b;Szwedziak et al.2012)

FtsZ (Loweand Amos1999;Popp et al.2010a;Strausset al. 2012)

SopA (Lim et al.2005)

Vignaud et al.2012

Mitchell 2004;Satir et al.2008

Severing Cooper andSchafer 2000

Sharp andRoss 2012

Branching Mullins et al.1998

Petry et al.2013

Dynamic overlapof antiparallelfibers

Bieling et al.2010

Molecular motors Vale andMilligan 2000

Kull et al. 1996





gation (Lim et al. 2005). Filaments formed bythe actin-like Alp7A also undergo dynamic in-stability, and computational modeling and ex-periments of an artificial system consisting ofAlp7A and a plasmid revealed how such dynam-ic instability can drive the positioning of plas-mids either to the cell center or the cell poles(Drew and Pogliano 2011). This bimodal systemis tunable, and cell-center or cell-pole position-ing depends on the parameters of dynamic in-stability. This simple system illustrates how adynamic cytoskeletal system of a few compo-nents can create spatial inhomogeneity of mac-romolecules in the cell.

Force Generation

The eukaryotic cytoskeleton can generate forceby at least three distinct mechanisms: filamentgrowth, filament shrinkage (Kueh and Mitchi-son 2009; McIntosh et al. 2010), or molecularmotors walking on filaments (Vale 2003). Inprokaryotes, no motor has been found, andforce is generated by filament growth, filamentshrinkage, or filament bending (FtsZ). Nucleo-tide-driven filament growth relies on the con-tinuous addition of subunits to the filamentend, which can push the attached structures.This is the general mechanism of force gen-eration for all three types of plasmid partition-ing systems. Filament shrinkage has also beensuggested as a mechanism of force generationduring chromosome segregation in Caulobactercrescentus. The shrinkage of the ParA filament,destabilized by centromere-bound ParB, isthought to move the centromere to the cell polesthrough a “burnt-bridge Brownian ratchet”mechanism (Ptacin et al. 2010). Filament bend-ing was proposed to exert force during FtsZ-mediated cell division (Osawa et al. 2009). Largefilaments formed by the overexpression of theactin-like protein, FtsA, can also bend Escheri-chia coli cells (Szwedziak et al. 2012).

Cooperation of Distinct Filament Types

In eukaryotes, the actin and tubulin systemsoften work together, for example, at the mid-body during cell division or during endocytosis

when cargo vesicles switch from actin- to mi-crotubule-based transport (Soldati and Schliwa2006). Cooperation of distinct filament typesalso occurs in prokaryotes. In C. crescentus, theCtpS and crescentin filaments co-occur at theinner cell curvature and regulate each other.Crescentin recruits CtpS, and CtpS negativelyregulates crescentin assembly (Ingerson-Maharet al. 2010). A two-filament system is also im-portant during FtsZ-mediated cell division.The tubulin-like GTPase forming the constric-tion ring, FtsZ, is recruited to the membraneby the actin-like protein FtsA. FtsA also formsfilaments, and this ability has been shown tobe important for proper cell division (Szwed-ziak et al. 2012). Polymerized FtsZ may be at-tached to the membrane by patches of poly-merized, membrane-bound FtsA localized tothe cell division ring. It has recently been foundthat FtsZ also directly interacts with MreB, andthis interaction is required for Z-ring contrac-tion and septum synthesis (Fenton and Gerdes2013).

Higher-Order Filament Structures

Eukaryotic filament systems generate severalhigher-order structures, including the ciliaryaxoneme, the mitotic spindle, microtubule as-ters, or contractile actin meshworks (Vignaudet al. 2012). Several prokaryotic filaments alsoform higher-order structures (Table 1). FtsZcan form toroids and multistranded helices,consisting of several filaments bundled together(Popp et al. 2010a). Pairs of parallel FtsZ fila-ments associated in an antiparallel fashion canform sheets (Lowe and Amos 1999). In vivo,FtsZ forms discontinuous patches in a bead-like arrangement at the cell division ring con-sisting of several filaments (Strauss et al. 2012).SopA is able to form aster-like structures in vi-tro, radiating from its binding partner, SopB,bound to a plasmid containing SopB-recogni-tion-sites (Lim et al. 2005). The actin-like pro-tein ParM is also able to form asters in vitro(Garner et al. 2007) and antiparallel filamentsin the cell (Gayathri et al. 2012). MreB formsmultilayered sheets with diagonally interwovenfilaments, or long cables with parallel protofila-

G. Jekely




ments (Popp et al. 2010c). Filaments of the ac-tin-homolog FtsA can also form large bundleswhen overexpressed in E. coli that can bend thecell and tubulate the membrane (Szwedziaket al. 2012). The bacterial actin AlfA can formthree-dimensional (3D) bundles, rafts, and nets(Popp et al. 2010b).

This list is impressive and illustrates wellthe versatility of the prokaryotic cytoskeleton.However, the complexity of the higher-orderstructures formed by the eukaryotic cytoskel-eton far surpasses the complexity of these struc-tures. The eukaryotic cytoskeleton organizescellular space using both dynamic scaffolds(e.g., mitotic spindle, microtubule aster, lamel-lipodia) and static scaffolds built of stabilizedfilaments (e.g., axoneme, microtubular ciliaryroot, microtubule-supported cell-cortex in sev-eral protists, stabilized microtubule bundles inmetazoan neurites, microvilli, sarcomeres). Theformation of these structures would not be pos-sible without the unique dynamic properties ofthe eukaryotic cytoskeleton.

Unique Dynamic Properties of the EukaryoticCytoskeleton

The eukaryotic cytoskeleton has several novelproperties, not yet described in prokaryotic fil-ament systems. These include filament sever-ing (actin fibers [Cooper and Schafer 2000] andmicrotubules [Sharp and Ross 2012]); branch-ing (actin fibers [Mullins et al. 1998] and micro-tubules [Petryet al. 2013]), and dynamic overlapof the antiparallel fibers (microtubules [Bielinget al. 2010]). In addition to these novel proper-ties, those properties that are shared by prokary-otic filaments also evolved additional layers ofregulation. A host of accessory cytoskeletal fac-tors appeared early in eukaryote evolution. Forexample, microtubule dynamics is regulated bynucleating (g-tubulin ring complex [g-TuRC]),stabilizing (MAPs), destabilizing (stathmin, ka-tanin), minus-end stabilizing (patronin/ssh4)(Goodwin and Vale 2010), and plus-end-track-ing proteins (Jiang and Akhmanova 2011). Sim-ilarly, actin dynamics is also regulated by a rangeof accessory factors, mostly representing eukary-

otic novelties (Rivero and Cvrckova 2007; Eckertet al. 2011).

The most dramatic innovation in eukary-otes is the use of molecular motors (Vale andMilligan 2000). Kinesins and myosins share acatalytic core that undergoes a conformationalchange on nucleotide binding and hydrolysis.This is transmitted by a “relay helix” to the poly-mer binding sites and the mechanical elements(Kull et al. 1996). Motor proteins are steppingalong the filaments using such mechanochem-ical cycles. Motors are either nonprocessive orprocessive, depending on whether they performone or multiple cycles before detaching fromthe filament. Processive motion enables long-range transport using one motor protein. A hy-pothetical evolutionary scheme for the evolu-tion of processive motors from a GTPase is out-lined in Figure 5.

The advent of motors added an extra layerof complexity to cytoskeletal dynamics. Motorsperform diverse and specialized functions andare essential for the movement of organelles andcomplexes (e.g., intraflagellar transport), estab-lishment of a bipolar spindle, definition of thecell division plane, cell migration, and cell po-larity. For example, specific kinesin families areinvolved in the regulation of ciliary transportand motility (kinesin 2, 9, 13), and only occurin species with cilia (Wickstead et al. 2010).Others are involved in ciliary length control(Kif19) (Niwa et al. 2012). Some kinesins regu-late different aspects of spindle organization in-cluding spindle midzone formation (kinesin-4,Kif14) (Kurasawa et al. 2004; Gruneberg et al.2006), alignment on the metaphase plate (Xkid)(Antonio et al. 2000), or centrosome separationduring bipolar spindle assembly (Eg5 [Kapiteinet al. 2005]; Kif15 [Tanenbaum et al. 2009]).

The eukaryotic cytoskeleton forms complex3D patterns by the dynamic interactions of fil-aments, motors and accessory proteins in a self-organizing process (Vignaud et al. 2012). Theevolution of these new dynamic properties musthave been tightly linked to the origin of novelcellular features during eukaryote origins. In thefollowing section, some of the possible links inthe framework of a cell evolutionary scenariowill be discussed.





COEVOLUTION OF A DYNAMIC ANDSCAFFOLDING CYTOSKELETON WITHEUKARYOTIC ORGANELLES

The origin of the eukaryotic cytoskeleton can beplaced into a transition scenario of eukaryoteorigins. Such scenarios may seem like “just-sostories,” but are nevertheless important concep-

tual frameworks and can identify problems forfuture research. The first major event that couldhave precipitated a functional shift in the pro-karyotic cytomotive filament systems couldhave been the loss of a rigid cell wall (Cavalier-Smith 2002). This step is necessary, irrespectiveof the prokaryotic lineage from which eukary-otes evolved (archaebacteria or the common

Force

Force

Vesicle

Vesicle

Dimeric motor

NTPase

A

B

C

Membrane

New binding site

Microtubule

Microtubule

Microtubule

Actin filament

Geneduplication

Nonprocessive step

Processive step

Nucleotide-dependent binding

Figure 5. Evolutionary scenario for the origin of processive kinesin and myosin motors. Kinesin and myosin havea common origin and evolved from a GTPase switch. In the first stage, the NTPase is bound to the filament in anucleotide-dependent manner via a short motif connected to the NTPase domain. The NTPase was engaged inother interactions (e.g., membrane binding), and recruited the filament to an organelle. In the next step, themechanical elements evolve that can perform one mechanical cycle following the nucleotide cycle. Motion anddissociation are both coupled to the nucleotide cycle and are transduced via a relay helix that is conservedbetween kinesin and myosin. This nonprocessive motor can now exert force on the bound organelle (e.g., avesicle). The clustering of several of these motors can move organelles. Monomeric motors may have beennonprocessive (Berliner et al. 1995), or may have used biased one-dimensional diffusion for processivity (Okadaand Hirokawa 1999). Myosin and kinesin probably diverged at such a stage by the acquisition of a novel filament-binding site and engagement with the second filament type (the direction is unclear). It is unlikely that thecommon ancestor of kinesin and myosin had a binding surface for both actin and tubulin filaments. Motordimerization may have evolved to increase the probability of repeated engagement with the filaments. Forprocessivity, the dimensions of the linker had to match the spacing of the accessible binding sites on the filament(80 A for microtubules, 360 A for actin filaments). This allowed the filament-dependent coupling of thenucleotide cycles on the two motor heads (the “mechanically controlled access” model) (Vale and Milligan2000).

G. Jekely




ancestor of the sister groups archaebacteria andeukaryotes). The loss of the cell wall may havebeen a dramatic, but not lethal event. The recentdiscovery of cell division in wall-free bacteria viamembrane blebbing and tubulation provides amodel for cell division following cell-wall loss(Mercier et al. 2013). Importantly, wall-free di-vision is independent of FtsZ, suggesting that inearly eukaryote evolution the release of func-tional constraints may have allowed the rapidfunctional evolution of FtsZ. Similarly, a rapidshift in prokaryotic actin functions may alsohave been facilitated by cell-wall loss.

MreB directly contributes to the mechanicalintegrity of the bacterial cell, independent of itsfunction in directing cell-wall synthesis (Wanget al. 2010). This suggests that the mechanicalfunction of the filamentous cytoskeleton mayhave a prokaryotic origin. Loss of the cell wallmay have triggered the elaboration of such afunction and led to the evolution of actin net-works involved in motility and cytokineses.

An important step in tubulin evolution wasthe origin of the microtubule, formed by thelateral association of protofilaments. Hollowtubes have higher mechanical rigidity and couldhave more efficiently served scaffolding andtransport functions. Microtubules may haveevolved into the 13-protofilament-form fol-lowing the origin of the g-TuRC complex thathelped to fix the number of protofilaments.

A common theme in the evolution of ac-tin and tubulin filaments is the early origin ofparalogs involved in nucleating the filaments(Arp2/3 and g-tubulin). FtsZ dimers can nu-cleate FtsZ filaments, and it is conceivable thata gene duplication event allowed the function-al separation and streamlining of the filament-forming and nucleating functions for both fil-ament types. The origin of separate nucleatingfactors allowed a more flexible positioning ofnucleating centers, given that these could nowbe regulated independent of the filaments.

By providing support for membrane trans-port, the filaments facilitated the evolution ofthe endomembrane system (Jekely 2003). Allendomembranes depend on cytoskeletal factorsfor their formation and transport. Early mem-brane dynamics may have evolved to allow en-

docytic uptake of fluid and particles and deliverextra membrane to sites of phagocytic up-take. Phagocytosis can proceed even without adynamic actin cytoskeleton, driven by thermalmembrane fluctuations and ligand-receptorbonds that zipper the membrane around a par-ticle. The origin of an actin network could havemade this process more efficient by preventingthe membrane from moving backward like aratchet (Tollis et al. 2010). The origin of phago-cytosis could have led to the origin of mito-chondria (Cavalier-Smith 2002; Jekely 2007).Energetic arguments seem to favor an early or-igin of mitochondria (Lane and Martin 2010);however, complex, nucleotide-driven dynamicfilament systems are abundant in prokaryotesand can drive membrane remodeling. For ex-ample, overexpression of the actin-like proteinFtsA can lead to the formation of large, protein-coated intracellular membrane tubules (Szwed-ziak et al. 2012). In addition, amitochondrialeukaryotes can maintain a complex cytoskele-ton (e.g., Trichomonas vaginalis has 19 kinesinand 41 dynein heavy chains), making the ener-getic argument for the primacy of mitochondriaover phagotrophy less compelling.

The self-organizing properties of the cy-toskeleton presumably evolved very early. Weknow from minimal systems and simulationsthat a few components are sufficient to organizecomplex, dynamic structures such as spindles,spirals, and aster (Leibler et al. 1997; Surrey2001; Nedelec 2002; Nedelec et al. 2003). Forexample, one function of the dynamically un-stable microtubule cytoskeleton is to positionthe nucleus in the cell center by exerting push-ing forces on the nucleus (Tran et al. 2001). Thisprocess contributes to the spatial organizationof the cell (e.g., by determining the cell divisionplane). Center positioning can also work in vi-tro with a minimal system of dynamic microtu-bules, even in the absence of motor proteins(Holy et al. 1997).

These examples illustrate that we have agrowing understanding of the self-organizationof dynamic cytoskeletal structures of variousshapes and functions. In future studies, thisknowledge could be combined with compara-tive genomic reconstructions to study “alter-





native cytoskeletal landscapes” in different eu-karyotic lineages (Dawson and Paredez 2013)and reconstruct the stepwise assembly of theseself-organizing structures during the origin ofeukaryotes.

CONCLUDING REMARKS

The complex self-organizing properties of thecytoskeleton set it apart from other cellular sys-tems such as large macromolecular assembliesor metabolic pathways. This means that it isdifficult to deduce what effects the additionor loss of one component might have had onthe systems-level properties. This is in contrastto metabolic pathways, in which evolutionarychanges can be efficiently modeled using flux-balance analysis of the entire metabolic networkof a cell (Pal et al. 2005). A similar analysis is notyet feasible for the entire cytoskeletal network.However, it would now be possible to study theevolution of subsystems from a systems perspec-tive. Consider the mitotic spindle. We have agood understanding of how the antiparallel mi-crotubule arrays overlapping at their plus endsform in a dynamic process involving an inter-play of microtubule growth and shrinkage, mo-tor activity, and proteins binding specificallyto the overlap region (Janson et al. 2007). Theemergence of a dynamic bipolar spindle can alsobe captured in computer simulations (Nedelec2002). In evolutionary models, one would haveto consider a succession of states following thegradual change of activities or addition of com-ponents. There are at least five ancestral kinesinfamilies involved in mitosis (Wickstead et al.2010). How did mitosis work when there wasonly one kinesin in a stem eukaryote?

The origin of axonemal motility, involvingmicrotubule doublets and at least seven ances-tral axonemal dynein families (Wickstead andGull 2007), represents a similar problem. Whatwas the beat pattern of the protocilium likewith only one axonemal dynein? How did itchange when inner-arm and outer-arm dyneinsdiverged? The origin of lamellipodial motilityand phagocytosis could also be best addressedby focusing on minimal systems that allow theformation of membrane protrusions supported

by an actin network (Gordon et al. 2012; Vig-naud et al. 2012). Only a combination ofmutant studies (Mitchell and Kang 1991), invitro reconstituted systems (Takada and Kamiya1994), comparative genomics (Wickstead andGull 2007), and computer simulations (Brokaw2004; Tollis et al. 2010) could answer these ques-tions.

ACKNOWLEDGMENTS

I thank David R. Mitchell and Elizabeth Wil-liams for their comments on the manuscript.The research leading to these results receivedfunding from the European Research Councilunder the European Union’s Seventh Frame-work Programme (FP7/2007-2013)/EuropeanResearch Council Grant Agreement 260821.

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2014; doi: 10.1101/cshperspect.a016030Cold Spring Harb Perspect Biol Gáspár Jékely Network of Eukaryotic OrganellesOrigin and Evolution of the Self-Organizing Cytoskeleton in the

Subject Collection The Origin and Evolution of Eukaryotes

FunctionEukaryotic Gen(om)e Architecture and Cellular The Persistent Contributions of RNA to

Jürgen Brosius

Mitochondrion Acquired?Eukaryotic Origins: How and When Was the

Anthony M. Poole and Simonetta Gribaldo

the Plant KingdomGreen Algae and the Origins of Multicellularity in

James G. Umen

Bacterial Influences on Animal OriginsRosanna A. Alegado and Nicole King

Phylogenomic PerspectiveThe Archaeal Legacy of Eukaryotes: A

Lionel Guy, Jimmy H. Saw and Thijs J.G. Ettemathe Eukaryotic Membrane-Trafficking SystemMissing Pieces of an Ancient Puzzle: Evolution of

Klute, et al.Alexander Schlacht, Emily K. Herman, Mary J.

OrganellesCytoskeleton in the Network of Eukaryotic Origin and Evolution of the Self-Organizing

Gáspár Jékely LifeIntracellular Coevolution and a Revised Tree ofOrigin of Eukaryotes and Cilia in the Light of The Neomuran Revolution and Phagotrophic

Thomas Cavalier-Smith

from Fossils and Molecular ClocksOn the Age of Eukaryotes: Evaluating Evidence

et al.Laura Eme, Susan C. Sharpe, Matthew W. Brown,

Consequence of Increased Cellular ComplexityProtein Targeting and Transport as a Necessary

Maik S. Sommer and Enrico Schleiff

SplicingOrigin of Spliceosomal Introns and Alternative

Manuel Irimia and Scott William Roy

How Natural a Kind Is ''Eukaryote?''W. Ford Doolittle

Eukaryotic Epigeneticsand Geochemistry on the Provenance ofImprints of Bacterial Biochemical Diversification Protein and DNA Modifications: Evolutionary

et al.L. Aravind, A. Maxwell Burroughs, Dapeng Zhang,

Insights from Photosynthetic EukaryotesEndosymbionts to the Eukaryotic Nucleus? What Was the Real Contribution of

David Moreira and Philippe Deschamps

Phylogenomic PerspectiveThe Eukaryotic Tree of Life from a Global

Fabien BurkiComplex LifeBioenergetic Constraints on the Evolution of

Nick Lane

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