The kinetochore–microtubule interface at a glanceJulie K. Monda1,2 and Iain M. Cheeseman1,2,*
ABSTRACTAccurate chromosome segregation critically depends on theformation of attachments between microtubule polymers and eachsister chromatid. The kinetochore is the macromolecular complexthat assembles at the centromere of each chromosome duringmitosis and serves as the link between the DNA and themicrotubules. In this Cell Science at a Glance article andaccompanying poster, we discuss the activities and molecularplayers that are involved in generating kinetochore–microtubuleattachments, including the initial stages of lateral kinetochore–microtubule interactions and maturation to stabilized end-onattachments. We additionally explore the features that contributeto the ability of the kinetochore to track with dynamic microtubules.Finally, we examine the contributions of microtubule-associated
proteins to the organization and stabilization of the mitotic spindleand the control of microtubule dynamics.
IntroductionCell division is a fundamental process that is carried out by allorganisms. During mitosis, the genetic material of each cell must beevenly distributed between both resulting daughter cells. The loss orgain of even a single chromosome can result in catastrophicconsequences for the organism (Schukken and Foijer, 2018). Toensure the accurate distribution of the DNA in eukaryotes, a largemacromolecular complex termed the kinetochore assembles onto thecentromere of each chromosome during mitosis. The architecture ofthe kinetochorewill not be extensively discussed in this Cell Science ata Glance article, but has been the topic of several recent review articles(Hara and Fukagawa, 2018; Hinshaw and Harrison, 2018; Joglekarand Kukreja, 2017; Musacchio and Desai, 2017; Nagpal andFukagawa, 2016; Pesenti et al., 2016). Instead, we will focus on theinterface between the kinetochore and microtubules, dynamicpolymers of tubulin heterodimers. This kinetochore–microtubule
1Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge,MA 02142, USA. 2Department of Biology, MIT, Cambridge, MA 02142, USA.
interface is critically important, as depolymerization of kinetochore-associated microtubules ultimately provides the driving force forchromosome segregation (Musacchio and Desai, 2017).Successfully harnessing the force released by microtubule
depolymerization and transducing that force to the DNA requiresa sufficiently stable kinetochore–microtubule attachment. Thegeneration of a stable microtubule attachment is not a trivial task.Within the vast expanse of the cytoplasm, the kinetochore mustlocate and bind to microtubules. If even a single kinetochore lacksmicrotubule attachments, the spindle assembly checkpoint willprevent anaphase onset (Rieder et al., 1995). Furthermore, thekinetochores of each sister chromatid must bind to microtubules thatemanate from opposing poles of the bipolar spindle to achieve astate termed bi-orientation. Kinetochore–microtubule interactionsare therefore initially highly dynamic to facilitate correction oferroneous attachments. Once bi-orientation is achieved, thekinetochore–microtubule attachment must be stabilized for forcetransduction, yet also remain sufficiently dynamic so as tomaintain itsassociation even as the microtubule polymerizes and depolymerizes.In this article and accompanying poster, we discuss the features andmolecular players that have key roles in overcoming these challengesin order to facilitate the formation of robust kinetochore–microtubuleinteractions. We focus on the kinetochore-localized proteins that bindmicrotubules, as well as proteins that alter the dynamics andorganization of kinetochore-bound microtubules.
Microtubule capture and lateral-to-end-on conversionAccurate chromosome segregation depends on the generation ofend-on kinetochore–microtubule interactions where the plus-end ofthe microtubule is embedded within the kinetochore. However,some kinetochores will initially associate with the side of themicrotubule, rather than the end (Barisic et al., 2014; Kapoor et al.,2006; Magidson et al., 2011; Tanaka et al., 2005). These lateralassociations are mediated by one of two kinetochore-localized,microtubule-based motors – cytoplasmic dynein and centromere-associated protein E (CENP-E). As a minus-end-directed motor,dynein transports chromosomes towards the spindle pole (Li et al.,2007; Vorozhko et al., 2008; Yang et al., 2007) and thereby towardsa region of high microtubule density. Chromosome congression isthen promoted by the plus-end directed activity of CENP-E(McEwen et al., 2001) (see poster). During mitosis, microtubuleplus-ends are located at both the cell cortex and equator (Prosser andPelletier, 2017). The directionality of CENP-E-driven chromosometransport is guided by tubulin detyrosination (Barisic et al., 2015), amodification that is found to be enriched in the equator-orientedmicrotubules of the mitotic spindle and depleted in the corticalmicrotubules (Gundersen and Bulinski, 1986). In this way, thecombined actions of dynein and CENP-E help to ensure timelychromosome alignment, and also promote the formation of end-onattachments by ensuring incorporation of the chromosomes into thespindle (Itoh et al., 2018) (see poster).To generate the initial lateral microtubule interactions,
kinetochores expand their reach by forming a structure that istermed the fibrous corona (Jokelainen, 1967; Magidson et al., 2015;McEwen et al., 1993; Rieder, 1982). A subset of outer kinetochoreproteins, including dynein (Wordeman et al., 1991), CENP-E(Cooke et al., 1997), CENP-F (Rattner et al., 1993; Zhu et al., 1995)and the Rod–ZW10–Zwilch (RZZ) complex (Rod is also known askinetochore-associated protein 1; KNTC1) (Basto et al., 2004; Starret al., 1998), form an extended crescent-shaped structure thatsurrounds the kinetochore in the absence of microtubules (Donget al., 2007; Echeverri et al., 1996; Hoffman et al., 2001; Thrower
et al., 1996), thereby creating a large platform to capturemicrotubules. In Xenoups oocytes, an even larger expansion thatincludes more kinetochore proteins has also been recently described(Wynne and Funabiki, 2015).
The eventual conversion from a lateral to an end-on attachment isregulated by the counteracting functions of Aurora B kinase andprotein phosphatase 2A (PP2A), and facilitated by the complexbetween Astrin (also known as SPAG5) and small kinetochore-associated protein (SKAP; also known as KNSTRN) (Shresthaet al., 2017) (Astrin–SKAP complex; see poster). Althoughgeometrically distinct from the final goal of end-on microtubuleattachments, the early establishment of kinetochore–microtubuleinteractions sets the stage for the subsequent mitotic events andhelps facilitate chromosome alignment at the metaphase plate.
Core kinetochore–microtubule interactionsMature end-on microtubule attachments are required forchromosome bi-orientation and satisfaction of the spindleassembly checkpoint (Kuhn and Dumont, 2017). The centralplayer in the formation of these stable attachments is the Ndc80complex, a component of the kinetochore scaffold 1 (KNL1)/Mis12/Ndc80 (KMN) network. The KMN network serves as thekey link between the microtubules and the DNA (see poster), as italso binds the DNA-associated inner kinetochore proteins CENP-Cand CENP-T (Gascoigne et al., 2011; Huis In ‘t Veld et al., 2016;Kim and Yu, 2015; Malvezzi et al., 2013; Nishino et al., 2013;Przewloka et al., 2011; Rago et al., 2015; Schleiffer et al., 2012;Screpanti et al., 2011). CENP-T further acts as a platform to expandthe microtubule-binding capacity of the kinetochore, as a singleCENP-T protein can recruit two Ndc80 complexes in addition to anentire complement of the KMN network (Huis In‘t Veld et al., 2016;Pekgoz Altunkaya et al., 2016; Rago et al., 2015). The precisestoichiometry of Ndc80 and the other components of thekinetochore–microtubule interface are likely to be central to thestructure, organization and functionality of these interactions.However, for simplicity, the accompanying poster primarilyfocuses on the core concepts, rather than attempting to define therelative and absolute molecular numbers.
To ensure proper microtubule interactions, the KMN network isregulated by a variety of mechanisms. For example, Ndc80 bindingto microtubules is negatively regulated by the RZZ complex in earlymitosis, and that inhibition is relieved by recruitment of dynein tothe kinetochore (Cheerambathur et al., 2013). The RZZ complexand dynein show dynamic localization to kinetochores, with RZZlocalization being highest at nuclear envelope breakdown, anddynein localization being highest later in prometaphase (Itoh et al.,2018). In this way, RZZ-mediated inhibition of Ndc80 likelyprevents the formation of stable end-on attachments early in mitosiswhen there is a high frequency of incorrect kinetochore–microtubule interactions (Cheerambathur et al., 2013), such assyntelic attachments –where both sister kinetochores are attached tothe same pole or merotelic attachments –where a single kinetochoreattaches to microtubules from both spindle poles (see poster).
In addition to regulation by RZZ, Ndc80 is also negativelyregulated by phosphorylation by mitotic kinases, including AuroraA and Aurora B (Cheeseman et al., 2002; Chmatal et al., 2015;DeLuca et al., 2006; Shrestha et al., 2017; Ye et al., 2015). Aurora-mediated phosphorylation decreases the affinity of Ndc80 formicrotubules (Cheeseman et al., 2006), thereby allowing forcorrection of aberrant kinetochore–microtubule interactions.Consistent with this, Ndc80 phosphorylation is highest inprometaphase and decreases in metaphase through the combined
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actions of two phosphatases, PP1 and the PP2A-B56 holoenzyme(Liu et al., 2010; Posch et al., 2010; Schleicher et al., 2017).However, recent work has also suggested that a subset ofphosphorylation sites are maintained by Aurora A throughoutmitosis to ensure proper microtubule dynamics (DeLuca et al.,2017). Thus, the proper segregation of the DNA relies on precisecontrol of the microtubule-binding activity of the KMN network.
Dynamic microtubule tip trackingDuring mitosis, the kinetochore needs to not only establish end-onmicrotubule attachments, but also maintain those attachments whilethe microtubule grows and shrinks. Indeed, associations withdynamic microtubules contribute to multiple aspects of mitosis. Forexample, in addition to motor-driven chromosome congression,as discussed above, depolymerization-coupled pulling onkinetochores also contributes to chromosome congression andrelies on the ability of the kinetochore to maintain its associationwith a depolymerizing microtubule (Auckland and McAinsh,2015). Additionally, chromosomes undergo oscillations duringmetaphase (Jaqaman et al., 2010; Skibbens et al., 1993), therebyrequiring one sister chromatid to associate with depolymerizingmicrotubules while the other sister chromatid associates withelongating microtubules. Finally, chromosome segregation duringanaphase is driven by the association of kinetochores withdepolymerizing microtubules (Musacchio and Desai, 2017).Although critically required for the formation of stablemicrotubule
attachments, the role of Ndc80 in microtubule tip tracking is lessclear. In vitro, Ndc80 complexes are unable to track depolymerizingmicrotubules (Schmidt et al., 2012) unless the complex is artificiallyoligomerized (McIntosh et al., 2008; Powers et al., 2009; Volkovet al., 2018). It is unclear how well this oligomerization mimics theorganization of the ∼14 Ndc80 complexes that bind to eachkinetochore microtubule in human cells (Suzuki et al., 2015), but itsuggests that Ndc80 contributes to the associations with dynamicmicrotubules. Indeed, the phosphorylation state of the Ndc80complex tunes the association of kinetochores with elongatingmicrotubules in vivo (Long et al., 2017).In fungi, the ring-like Dam1 complex facilitates processive
microtubule interactions by binding both Ndc80 and themicrotubule, and sliding along the microtubule as protofilamentspeel away during depolymerization (Grishchuk et al., 2008;Lampert et al., 2010; Miranda et al., 2005; Tien et al., 2010;Westermann et al., 2005). Interestingly, this mechanism is notwidely conserved, as metazoans do not contain homologs of theDam1 complex (van Hooff et al., 2017). Instead, in species lackingthe Dam1 complex, the spindle and kinetochore-associated protein1 (Ska1) complex likely serves as a functional analog (Gaitanoset al., 2009; Welburn et al., 2009), although the Ska1 complex doesnot form a ring-like structure (Monda et al., 2017; Schmidt et al.,2012; Welburn et al., 2009).Ska1 is recruited to the kinetochore by the Ndc80 complex
(Cheerambathur et al., 2017; Janczyk et al., 2017), and thephosphatases PP1 and PP2A also promote accumulation of Ska1at aligned kinetochores (Sivakumar and Gorbsky, 2017) (seeposter). Indeed, the levels of kinetochore-localized Ska1 increasethroughout congression, thereby enhancing the ability of maturekinetochore–microtubule attachments to sustain load-bearing forces(Auckland et al., 2017). In vitro, Ska1 autonomously tracks bothdepolymerizing and elongating microtubules (Monda et al., 2017;Schmidt et al., 2012), supporting the model that Ska1 contributes tothe ability of the kinetochore to generally associate with dynamicmicrotubules (Helgeson et al., 2018).
In addition to Ska1, other factors may contribute to dynamicmicrotubule interactions. For example, CENP-F also tracksdepolymerizing microtubules in vitro (Volkov et al., 2015).Taken together, the integrated microtubule-binding activities ofSka1, the Ndc80 complex and perhaps other proteins createthe dynamic interface required for persistent association withmicrotubules (see poster).
Stabilization of end-on attachmentsCycles of microtubule polymerization and depolymerizationgenerate forces that can be transmitted through the kinetochore todrive chromosome movement. Withstanding and harnessing thatforce requires the kinetochore–microtubule attachment to besufficiently robust and stable. Although the Ndc80 complex iscritical for the formation of microtubule attachments (Cheesemanet al., 2006; DeLuca et al., 2006), other microtubule-bindingproteins play key roles in stabilizing and strengthening thosemicrotubule interactions. First, the microtubule-bound Ska1complex strengthens Ndc80-mediated microtubule interactionsand is capable of bearing load (Cheerambathur et al., 2017;Helgeson et al., 2018), in addition to its role in tracking dynamicmicrotubules (Monda et al., 2017; Schmidt et al., 2012). Second,the Astrin–SKAP complex specifically localizes to microtubule-attached and bi-oriented kinetochores, where it binds tomicrotubules synergistically with Ndc80 (Kern et al., 2017) (seeposter). Thus, the activities of Ndc80, Ska1, Astrin–SKAP andpotentially other proteins, create a stable kinetochore–microtubuleinterface that is capable of withstanding the significant force exertedby the mitotic spindle.
Kinetochore-fiber organizationIn most organisms, each kinetochore binds a bundle of multiplemicrotubules (∼17 in human cells; McEwen et al., 2001; Wendellet al., 1993), collectively referred to as a kinetochore fiber (denotedk-fiber). In contrast to other populations of mitotic microtubules,k-fibers are uniquely stable, as evidenced by their persistence aftercold treatment (Salmon and Begg, 1980). This enhanced stability isthe result of their plus-ends being embedded within kinetochores,and the cross-linking and bundling of adjacent microtubules. Thecomplex comprising transforming complex acidic coiled-coil-containing protein 3 (TACC3), colonic and hepatic tumoroverexpressed gene protein (ch-TOG; also known as CKAP5) andclathrin, stabilized by phosphatidylinositol 4-phosphate 3-kinaseC2 domain-containing subunit α (PI3K-C2α; encoded byPIK3C2A) (Gulluni et al., 2017), crosslinks microtubules andcontributes to the organization of the mitotic spindle (Booth et al.,2011; Nixon et al., 2017). K-fiber stabilization is also achievedthrough the microtubule-bundling activity of hepatoma up-regulated protein (HURP; also known as DLGAP5) (Koffa et al.,2006; Silljé et al., 2006; Wong and Fang, 2006) (see poster).Together, the stabilization and organization of k-fibers by theseproteins ultimately allows for the generation of sufficient force todrive accurate chromosome segregation.
Control of microtubule dynamicsChromosome congression, bi-orientation and segregation dependon precise regulation of the stability and dynamics of themicrotubules in the mitotic spindle. This balance is achievedthough the combined actions of numerous proteins that bothpositively and negatively regulate microtubule growth throughdiverse mechanisms. Regulators that localize at or near kinetochoresinclude the kinesin-like protein Kif18A (Mayr et al., 2007), mitotic
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centromere-associated kinesin (MCAK; also known as KIF2C)(Wordeman and Mitchison, 1995), ch-TOG (Gergely et al., 2003),cytoplasmic linker protein 170 (CLIP-170; also known as CLIP1)(Dujardin et al., 1998), and the CLIP-associating protein (CLASP)(Maiato et al., 2003) and end-binding (EB or MAPRE) (Juwanaet al., 1999) families of microtubule-binding proteins (see poster).Metaphase chromosome oscillations are regulated by thekinetochore-localized kinesin Kif18A, which suppressesmicrotubule dynamics (Du et al., 2010; Stumpff et al., 2008,2012). At anaphase onset, Kif18A and other factors must bedephosphorylated to allow for a switch from oscillations to robustpoleward movement of the separated sister chromatids (Su et al.,2016). MCAK is a kinesin-13 family member (Lawrence et al.,2004) and a microtubule depolymerase (Desai et al., 1999; Hunteret al., 2003). By promoting microtubule depolymerization atkinetochores that are not yet bi-oriented and stably associatedwith the microtubule, MCAK facilitates the correction of erroneouskinetochore–microtubule attachments and thereby increase thelikelihood of achieving bi-orientation (Kline-Smith et al., 2004).The activity of MCAK is counteracted by ch-TOG, a highlyprocessive microtubule polymerase (Brouhard et al., 2008). CLIP-170 and CLASPs also promote microtubule growth, with CLIP-170promoting the transition from microtubule depolymerization tomicrotubule polymerization (Komarova et al., 2002) and CLASPspromoting the incorporation of tubulin subunits into k-fibers(Maiato et al., 2005). The EB family of proteins, comprising EB1,EB2 and EB3 (also known as MAPRE1, MAPRE2 and MAPRE3,respectively) in mammals (Su and Qi, 2001), are autonomous plus-end-tracking proteins (Bieling et al., 2007) that recruit a variety ofother proteins that contain cytoskeleton-associated proteins (CAP)-Gly domains or SxIP motifs (Kumar and Wittmann, 2012) to affectmicrotubule growth or organization (Browning et al., 2003;Komarova et al., 2005; Mimori-Kiyosue et al., 2005; Niethammeret al., 2007; Su et al., 1995) (see poster).The functions of these regulators of microtubule dynamics are also
subject to regulatory control themselves. For example, MCAK isphosphorylated by numerous mitotic kinases (Andrews et al., 2004;Lan et al., 2004; Ohi et al., 2004; Sanhaji et al., 2010; Zhang et al.,2007, 2011). Recent work has demonstrated that CDK1-mediatedphosphorylation of a single threonine residue in the MCAK motordomain is sufficient to block the ability of MCAK to distinguish theend of themicrotubule from the lattice, and thereby reducemicrotubuledepolymerization (Belsham and Friel, 2017). Additionally, MCAKundergoes significant structural rearrangements upon binding amicrotubule that allow for optimal depolymerase activity (Burnset al., 2014; Ems-McClung et al., 2013; Talapatra et al., 2015).Collectively, these diverse microtubule-associated proteins facilitatecell division by ensuring a dynamic mitotic spindle.
Conclusions and perspectivesDuring every cell division, numerous kinetochore-localizedmicrotubule-binding proteins must act to ensure the accuratesegregation of the DNA to the daughter cells. A stable, bipolarspindle must be built, the kinetochore of each sister chromatid mustattach to microtubules emanating from one of the spindle poles, andeach kinetochore must be capable of maintaining its microtubuleattachment, despite elongation and depolymerization of themicrotubule. Recent work has defined numerous molecularplayers that are involved in each of these key aspects of mitosis.Given the complexity of the kinetochore, it is perhaps unsurprisingthat many of these proteins have opposing activities: dynein andCENP-E transport chromosomes in opposite directions, Astrin–
SKAP must stabilize the kinetochore–microtubule attachmentsyet also allow for dynamic interactions and Ska1-mediated tip-tracking, and MCAK destabilizes microtubules, whereas ch-TOG,CLIP-170 and CLASPs promote microtubule growth. A key goalfor future studies will therefore be to uncover how the diverseactivities of these molecules are integrated to ensure faithfulchromosome segregation.
AcknowledgementsWe thank Leah Bury, Nolan Maier, Lily McKay and Gunter Sissoko for criticallyreading and providing comments on this manuscript. We apologize to the manyauthors whose work we could not include due to space restrictions.
Competing interestsThe authors declare no competing or financial interests.
FundingWork in the Cheeseman laboratory is supported by grants from G. Harold and LeilaY. Mathers Charitable Foundation and the National Institute of General MedicalSciences (GM088313 and GM108718). Deposited in PMC for release after 12months.
Cell science at a glanceA high-resolution version of the poster and individual poster panels are available fordownloading at http://jcs.biologists.org/lookup/doi/10.1242/jcs.214577.supplemental
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