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FOLLOWING THE EVOLUTION OF NEW PROTEIN FOLDS VIA PROTODOMAINSSpencer Bliven
January 28, 2013
Advancement to Candidacy Exam
CATH:http://www.cathdb.info/browse/browse_hierarchy
http://scop.mrc-lmb.cam.ac.uk/scop/
Grishin. J Struct Biol (2001) vol. 134 (2-3) pp. 167-85
Sadreyev, R. I., Kim, B.-H., & Grishin, N. V. (2009). Discrete-continuous duality of protein structure space. Current Opinion in Structural Biology, 19(3), 321–328.
CONTINUITY
Orengo, Flores, Taylor, Thornton. Protein Eng (1993) vol. 6 (5) pp. 485-500
Holm and Sander. J Mol Biol (1993) vol. 233 (1) pp. 123-38
Holm and Sander. Science (1996) vol. 273 (5275) pp. 595-603
Shindyalov and Bourne. Proteins (2000) vol. 38 (3) pp. 247-60
Hou, Sims, Zhang, Kim. PNAS (2003) vol. 100 (5) pp. 2386-90
Taylor. Curr Opin Struct Biol (2007) vol. 17 (3) pp. 354-61
Sadreyev et al. Curr Opin Struct Biol (2009) vol. 19 (3) pp. 321-8
α
α+β
β
α/β
MODELS OF FOLD SPACE
BIG QUESTIONS
Is fold space discrete or continuous?
Where do new folds come from?
What insights can we gain by studying fold space?
DEFINITIONS
BIOLOGICAL ASSEMBLIES
Asymmetric Unit
Biological Assembly
Sesbania mosaic virus [1VAK]
Hemoglobin [1hv4]
DOMAINS
Compact Geometry Independently Folding
Non-contiguous domains Multi-chain domains
Kunitz-type trypsin inhibitor [1r8o]
Squalene-Hopene Cyclase [1SQC]
FOLD
Group of domains with Same major secondary structural elements Same mutual orientation Same connectivity
PROTODOMAINS
A protodomain is a minimal, independently evolving protein unit with a conserved structure.
Defined through evolution, but usually observed as structural motif
Coined by Philippe Youkharibache
PROTODOMAINS
A protodomain is a minimal, independently evolving protein unit with a conserved structure.
Glyoxalase I from Clostridium acetobutylicum [3HDP]
GTP binding regulator from Thermotoga maritima [1VR8]
Glyoxalase I in E. coli [1F9Z]
Pseudomonas 1,2-dihydroxy-naphthalene dioxygenase [2EHZ]
PROPOSAL
SPECIFIC AIMS
1. Improve algorithms to identify conserved protodomains globally across the PDB.
2. Identify structurally similar and potentially homologous protodomains across fold space.
3. Integrate protodomain arrangements with domain and quaternary structure information to create a parsimonious model of fold evolution across the tree of life.
4. Apply protodomain principles to understanding the evolution of specific protein families.
AIM 1
Improve algorithms to identify conserved protodomains globally across the PDB.
Preliminary Research:a) Circular Permutation with CE-CPb) Symmetry with CE-Symm
Proposed Research:c) Improve CE-Symm algorithmd) Create algorithms for other types of
protodomain rearrangementse) Run algorithms globally across the PDBf) Create non-redundant catalogue of
protodomains
CIRCULAR PERMUTATION
Spencer Bliven and Andreas Prlić. Circular Permutation in Proteins. PLoS Comput Biol (2012) 8(3): e1002445.
CIRCULAR PERMUTATION EVOLUTION
Fission & Fusion Permutation by Duplication
CE-CP A Prlić, S Bliven, P Rose, J Jacobsen, PV Troshin, M Chapman, J Gao,
CH Koh, S Foisy, R Holland, G Rimša, ML Heuer, H. Brandstätter–Müller, PE Bourne, and S Willis. BioJava: an open-source framework for bioinformatics in 2012. Bioinformatics (2012).
http://www.rcsb.org/pdb/workbench/workbench.do
Concanavalin A [1NLS.A] vs. Pea Lectin [1RIN.A+B]
NC
N
C
Molybdate-binding protein [1ATG.A] vs. OpuAC [2B4L.A]
Regulator of G protein signaling 10 [2IHB.A] vs.
vaccinia H1-related phosphatase [1VHR.A]
DETECTING CIRCULAR PERMUTATIONS
SYMMETRY
Goodsell, D. S., & Olson, A. J. (2000). Structural symmetry and protein function. Annual Review of Biophysics and Biomolecular Structure, 29, 105–153.
Beta Propeller
SYMMETRY
Functionally important Protein evolution (e.g. beta-trefoil) DNA binding Allosteric regulation Cooperativity
Widespread (19% of proteins)
TATA Binding Protein1TGH
Hemoglobin4HHB
FGF-13JUT
SYMMETRY EVOLUTION
Start with perfectly symmetric homomer Duplications & Fusions Symmetry lost to drift
INTERMEDIATES TO BETA-TREFOIL
Lee, J., & Blaber, M. (2011). Experimental support for the evolution of symmetric protein architecture from a simple peptide motif. PNAS, 108(1), 126–130.
FGF-1 [3JUT]
CE-SYMM WISHLIST
Find alignments for all valid rotations Refine alignments based on
isomorphism constraints Utilize crystallographic symmetry
more efficiently for biological assemblies
Detect multiple axes of symmetry
Triose Phosphate Isomerase [8TIM]
5-enol-pyruvyl shikimate-3-phosphate (EPSP) synthase [1G6S]
CE-SYMM
Andreas Prlić, Spencer E. Bliven, Peter W. Rose, Philippe Youkharibache, Douglas Myers-Turnbull, Philip E. Bourne. On Symmetry and Pseudo-Symmetry in Proteins. In preparation.
AmtB [3C1G]FGF-1 [3JUT]
CE-SYMM
FGF-1
CE-SYMM
FGF-1
ADDITIONAL METHODS FOR DETECTING PROTODOMAINS
Changes in Quaternary Structure
Protodomain searches (Douglas Myers-Turnbull)
Domain Swapping
AIM 2
Identify structurally similar and potentially homologous protodomains across fold space.
Preliminary Researcha) All-vs-all comparison of chains & domainsb) Clustering & network analysisProposed Researchc) Run all-vs-all comparison of protodomainsd) Build protodomain similarity networke) Correlate network with existing properties:
ligand binding, symmetry order, enzymatic activity, and distribution across organisms, etc
ALL-VS-ALL STRUCTURAL ALIGNMENT
Andreas Prlić, Spencer Bliven, Peter W Rose, Wolfgang F. Bluhm, Chris Bizon, Adam Godzik, Philip E. Bourne. Precalculated Protein Structure Alignments at the RCSB PDB website. Bioinformatics (2010) vol. 26 (23) pp. 2983-2985
ALL-VS-ALL STRUCTURAL ALIGNMENT
Use sequence clustering to get representative chains with <40% sequence identity (currently 23410)
Split into domains by SCOP or PDP All chains and domains compared using
FATCAT Use Open Science Grid (OSG) Client/Server architecture for aggregating
results
Scores
…
…
NETWORK FROM TRANSPORTER CLASSIFICATION DATABASE (TCDB)
Primary Active TransportersChannels/PoresTransmembrane Electron CarriersGroup Translocators…
C4
C5
C6
C7
Symmetry
BETA PROPELLERS
CROSS-CLASS EXAMPLE
3GP6.A PagP, modifies lipid A f.4.1 (transmembrane
beta-barrel)
1KT6.A Retinol-binding
protein b.60.1 (Lipocalins)
AIM 3 Integrate protodomain arrangements with domain
and quaternary structure information to create a parsimonious model of fold evolution across the tree of life.
Preliminary Researcha) Classification of biological assemblies by quaternary
symmetry & chain stoichiometryb) Model for evolution via protodomainsProposed Researchc) Determine the protodomain content of each
biological assemblyd) Identify BAs with conserved protodomain architecture
but different chain architecture, or vice versae) Integrate data with model of protodomain evolution
QUATERNARY STRUCTURE
Find symmetry & pseudosymmetry within biological assemblies
Functions at chain level Can use various thresholds to determine
stoichiometry (95% sequence, CE alignment, etc)
Hemoglobin [4HHB]C2 (2,2)
GTP Cyclohydrolase I [1A8R] D5
(10)
Rhinovirus 2 [3DPR]I (60,60,60,60,60)
EVOLUTIONARY MODEL
1. Local Mutation2. Protodomain fusion3. Protodomain fission4. Loss of Interface5. Gain of Interface6. New Protodomains
CONNECTION TO FOLD SPACE
Mostly local mutations = continuous regions Protodomain creation & rearrangement =
discrete regions Identifying evolutionary events allows
quantitative comparison of the frequencies of each mechanism
Biologically rather than geometrically motivated
AIM 4
Apply protodomain principles to understanding the evolution of specific protein families.
Qualities Have good structural coverage Contain multiple members with symmetry at
either domain or quaternary structure level. Contain circularly permuted members Span a diverse set of folds
Ion Channels Beta Propellers
AmtB [3C1G]
SODIUM/ASPARTATE SYMPORTER FROM PYROCOCCUS HORIKOSHII (GLTPH)
Forrest, L. R., Krämer, R., & Ziegler, C. (2011). The structural basis of secondary active transport mechanisms. Biochimica et Biophysica Acta, 1807(2), 167–188.
cytoplasm
[2NXW]
Top Side
CONCLUSIONS
Biological Assemblies are the functional unit of structure
Protodomains can rearrange without modifying the biological assembly
Separating changes in biological assembly from genetic changes can provide evolutionary perspective on fold space Local Changes = Continuous Evolution Protodomain rearrangements = Discrete
Transitions
TIMELINE
PUBLICATIONS A Prlić, S Bliven, PW Rose, WF Bluhm, C Bizon, A Godzik, PE
Bourne. Precalculated Protein Structure Alignments at the RCSB PDB website. Bioinformatics (2010) vol. 26 (23) pp. 2983-2985
Spencer Bliven and Andreas Prlić. Circular Permutation in Proteins. PLoS Comput Biol (2012) 8(3): e1002445.
A Prlić, S Bliven, P Rose, J Jacobsen, PV Troshin, M Chapman, J Gao, CH Koh, S Foisy, R Holland, G Rimša, ML Heuer, H Brandstätter–Müller, PE Bourne, and S Willis. BioJava: an open-source framework for bioinformatics in 2012. Bioinformatics (2012).
Intended: CE-Symm method Evolutionary model & examples of protodomain evolution Structural similarity network analysis Use of model for specific protein family
ACKNOWLEDGMENTS
CommitteePhilip BourneMilton H. SaierRussell F. DoolittleMichael K. GilsonAdam Godzik
Bourne Lab/PDBAndreas PrlićPeter RoseDouglas Myers-TurnbullLab & PDB members
CollaboratorsPhilippe
YoukharibacheJean-Pierre ChangeuxBiojava Contributors
The lovely Christine Bliven
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