Following the Evolution of New Protein Folds via Protodomains

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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