Post on 10-May-2015
description
The Evolution of Protein FoldsSpencer Bliven
Department of BioinformaticsUniversity of California San Diego
Andreas PrlićSan Diego Supercomputer CenterUniversity of California San Diego
Philip BourneSkaggs School of Pharmacy and Pharmaceutical Sciences
University of California San Diego
Methods1.Identification of domain and subdomain architecture
a.Use SCOP domains where available, or calculate using the Protein Domain Parser (PDP) algorithm
b.Detect symmetry using CE-Symm (manuscript in preparation)
c.Detect circular permutations using CE-CP (Shindyalov, 2000; Prlic, 2010)
2.All-vs-all structural similarity calculationa.Filter representatives to 40% sequence identity
b.Use FATCAT algorithm (Ye and Godzik, 2003) to compare all protein domains from the Protein Data Bank (nearly 1 billion alignments, accessible from http://www.pdb.org)
3.Network analysisa.Filter out low-scoring structural alignments (TMScore≥0.5, Length≥25,
Coverage≥60%)
b.Map functional properties onto nodes: SCOP/CATH classification, GO terms, symmetry order, ligand information, etc.
4.Phylogenetic analysis (planned)Future work will center on quantifying the prevalence of subdomain rearrangement by integrating evolutionary data with the structural comparison data.
The nature of protein fold space is hotly debated. Do the protein folds observed in nature fall into clean, discrete clusters, or is fold space more accurately modeled as a vast continuum, of which only a small sample of proteins has yet been observed? Previous efforts to answer this question have focused on geometric spaces (PCA, multidimensional scaling, locally linear embedding) or network models (conformational space networks) (Chodera, 2011). While such schemes may facilitate protein comparison and classification, the choice of a mathematical framework for fold space is arbitrary without a connection to concrete biological processes. To accurately capture the true relationships between protein folds, a model must consider the evolutionary history of those folds.
Here we present a high-level model of protein evolution, which focuses on mutations that preserve the global 3D structure of proteins. We hypothesize that the combination of subtle local changes (e.g. PTMs) and large, but structure-preserving, rearrangements (e.g. duplications) can account for both the continuity of intermediate structures within protein folds and the evolution of seemingly novel folds. Our model categorizes known biological mutation processes, such as DNA replication errors and crossover errors, and places them in a simple theoretical framework.
To test this model, we present evidence from the analysis of a recent systematic comparison of all protein domains from the Protein Data Bank (PDB). We also show that the model is consistent with existing evolutionary models for gene duplication, circular permuted proteins, and proteins with internal symmetry. Future work will focus on explicitly determining evolutionary events relating distantly homologous folds.
Abstract
Poster first presented at the 20th Annual International Conference on Intelligent Systems for Molecular Biology (2012). Funded in association with the Protein Data Bank. The presentation of this work was made possible by a Travel Fellowship awarded by ISCB with grant funds obtained from the NIH NIMGS-National Institute of General Medical Sciences.
This work is licensed under the Creative Commons Attribution-NonCommercial 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc/3.0/ or send a letter to Creative Commons, 444 Castro Street, Suite 900, Mountain View, California, 94041, USA.
Model for the Evolution of New FoldsGiven these observations, we hypothesize that structure-preserving rearrangements are a major mechanism for the evolution of new protein folds. To test this, we classify mutations into the following categories:
1.Gene fusionA gene fusion occurs when two previously independent protein sequences are joined to create a single peptide product. This includes duplications, where the source sequence are identical, as well as the creation of chimeric proteins. To preserve function, the source proteins should either interact or form independently folding domains; other fusions are likely to be selected against.
2.Gene fissionA single peptide may split into two independently transcribed peptides. While a fission may be accompanied by the loss of the protein-protein interface, fissions which maintain the global structure of the protein are likely to be selected for.
3.Gain of protein-protein interfaceThe evolution of a new protein-protein interface results in a new quaternary structure. This may be either a heteromer, as shown in the diagram, or a homomer.
4.Loss of protein-protein interfaceProtein-protein interfaces may also be lost. This may occur in conjunction with fission.
5.Non-architectural mutationsAny mutation which does not alter the number of domains, binding, or connectivity is termed a non-architectural mutation. This includes insertions, deletions, and substitutions of amino acids or even whole secondary structures.
6.Order-disorder transitionsFor completeness, order-disorder transitions are included as a possible source of novel folds. However, such transitions are extremely difficult to detect, and are indistinguishable from primordial folds by the methods used in this study.
Principles of Protein Evolution1. Global structure is conserved in many significant rearrangements
2. Domains and subdomains are reused for many functions
(a) The TorD chaperon from Shewanella massilia (1N1C) is a dimer, but instead of each chain folding into a compact domain, each chain contributes to the structure or each domain. (b) The DmsD protein from Salmonella typhimurium (1S9U) has a very similar structure and has 20% sequence identity, but forms a monomer (Sippl, 2009).
(a) (b)
Domain Swapping Circular Permutation Symmetry(a)
(b) (c)
(a) Alignment of Regulatory Protein A from Human papillomavirus (1A7G) with AppA BLUF domain from Rhodobacter sphaeroides (2IYG). The two structures are related by a circular permutation, as can be seen from the rainbow coloring in (b) and (c)
The symmetric protein FGF-1 (3JUT), colored to highlight the 3-fold symmetry. Evidence suggests that ß-trefoils may have evolved from a trimeric precursor (Lee, 2011).
GTP binding regulator from Thermotoga maritima [1VR8] consists of two αβββ motifs, colored orange and yellow. The half-glyoxalase query motif (cyan) is aligned for comparison.
Structure of glyoxalase I from E. coli [3HDP]. Colors show the two-fold symmetry of the protein around its nickel-binding site.
Dimer form of glyoxalase I [1F9Z], colored by chain. Relative to 3HDP, the symmetric motifs are swapped between chains.
1,2‑dihydroxynaphthalene dioxygenase [2EHZ] from Pseudomonas (orange/grey) consists of four copies of the half-glyoxalase motif (cyan). Iron is bound at the active site.
FusionFission
Loss of interface
Gain of interface
ConclusionWe aim to provide a model for analyzing protein fold space based not on geometric properties, but on evolutionary relationships. This approach avoids the dichotomy of "continuous" and "discrete". Our model is derived from the observation that many proteins which are currently classified as belonging to separate folds can be decomposed into subdomains which appear in many different subdomain architectures.
The evolution of protein symmetry is a prime example of this phenomenon. Proteins may be symmetric at the level of quaternary structure, tertiary structure, or both. Significant homology can often be detected between the repeated subunits of symmetric proteins, suggesting that symmetry evolves by duplication and fusion events. These events preserve the protein-protein interaction interfaces and the global structure of the protein, providing a plausible pathway for radical fold change without non-functional intermediates. Likewise, the currently accepted models for the evolution of circular permutations can be couched as a special case of the model presented here (Weiner, 2006).
To investigate the evolution of protein folds as broadly as possible, an extensive all-vs-all comparison of domains from the Protein Databank was conducted. This consisted of nearly one billion pairwise alignments, and was performed on the Open Science Grid distributed cluster. This wealth of data allows the clustering of potentially homologous domains. Research is ongoing to incorporate evolutionary information into this network, with the ultimate goal of quantifying the prevalence of each mechanism for fold evolution.
Chodera & Pande (2011) PNAS. vol.108(32) pp. 12969–12970
Lee & Blaber (2011) PNAS, vol.108 (1) pp. 126–130Prlic et al. (2010) Bioinformatics. vol. 26 (23) pp.
2983-2985
Shindyalov and Bourne (2000) Proteins. vol. 38 (3) pp. 247-60
Sippl (2009) Curr Opin Struct Biol. vol.19 (3) pp. 312-20
Thornalley (1993) Mol. Aspects Med. 14 (4) pp. 287–371Ye and Godzik (2003). Bioinformatics. vol. 19(Suppl 2),
pp. ii246–55.Weiner & Bornberg-Bauer (2006) Mol. Biol. Evol. vol.
23(4) pp. 734–743
Case Study: Transmembrane Proteins
(Left) Structural similarities between domains of transmembrane proteins, as classified by the Transporter Classification Database (TCDB). A moderate threshold of TM‑Score≥0.5 was used, leaving the network fairly sparse. The nodes are colored according to their TCDB classification.
(Right) Enlargement of the boxed section of the graph, with 3D structures overlaid. All structures are similar to the Rossmann fold, but several are classified in different SCOP folds (e.g. PTS system IIB component-like (d1iiba_)). A wide diversity of TCDB functions are annotated to the structurally similar cluster.
PDP:2AEFAa PDP:3IPRAa
PDP:2FN9Ab
d1iiba_
d2r4qa1
PDP:3L9WAa
d1pdoa_
PDP:3A1DAa
d1djla_d1shux_
d1d4oa_
d1nrjb_
PDP:2IYEAa
PDP:2FN9Aa
PDP:2ZXEAa
PDP:2VOYIa
d1wa5a_
PDP:3QELBa
PDP:3QELBb
PDP:2O1EAb
d1nrza_
PDP:2OSVAa
PDP:2OSVAb
PDP:3HH8Aa
PDP:2O1EAa
PDP:3HH8Ab
PDP:3IPCAb
PDP:2Q8PAa
d1id1a_
d2hmva1
PDP:2WI8Aa
PDP:3QJGAa
PDP:3P2YAb
d1ls1a2
PDP:2FEWBa
PDP:3RBZAb
d1vkra_PDP:2VQ3Aa
PDP:3IPCAa
1.0
0.90.8
0.7
Transmembrane Electron Carriers
Channels/Pores
Incompletely Characterized
Transport Systems
Group Translocators
Accessory Factors Involved
in Transport
Primary Active
Transporters
Electrochemical Potential-driven
Transporters
Legend:Color indicates TCDB ClassEdge weight indicates TM-Score
0.5
0.64
0.52
0.57
0.54
0.53 0.530.58 0.65
0.66
0.75
0.65
0.52
0.53
0.63
0.57
0.55
0.75
0.58
0.60.56
0.64
0.73
0.730.61
0.66
0.71
0.59
0.58
0.77
0.5
0.64
0.52
0.5
0.51
0.54
0.6
0.530.67
0.60.7
0.67
0.53
0.51
0.66
0.560.61
0.6
0.650.52
0.54
0.58
0.7
0.520.69
0.77
0.57
0.56
0.53
0.5
0.76
0.54
0.610.65
0.560.59
0.55
0.570.61
0.55
0.69
0.5
0.550.670.65
0.54
0.58
0.64
0.5
0.53
0.68
0.56
0.51
0.5
0.52
0.61
0.530.55
0.62
0.620.58
0.61
0.5
0.67
0.8
0.58
0.84
0.69
0.690.68
0.52
0.6
0.56
0.550.6
0.60.55
0.550.55
0.560.52
0.58
0.55
0.510.67
0.55
0.680.62
0.58
0.7
0.67
0.56
0.64
0.650.55
0.640.61
0.57 0.50.67
0.62
0.72
0.51
0.64
0.53
0.69
0.58
0.62
0.56
0.56
0.5
0.5
0.6
0.51
0.53
0.84 0.510.780.7
0.60.78
0.54
0.52
0.5
0.530.5
0.540.52
0.62
0.62
0.560.55
0.55
0.69
0.61
0.6
0.72
0.81
0.58 0.87
0.58
0.78
0.61
0.52
0.85
0.57
0.53
0.530.74
0.55
0.790.81
0.84
0.670.68
0.61
0.67
0.73
0.59
0.77
0.57
0.59
0.81
0.88
0.5
0.57
0.57
0.6
0.65
0.71
0.59
0.50.57
0.54
0.620.53
0.660.65
0.57
0.74
0.51
0.58
0.590.69
0.7 0.76
0.72
0.8
0.87
0.53
0.830.73
0.7
0.62
0.76
0.660.67
0.70.58
0.6
0.6
0.690.78
0.66
0.53
0.54
0.670.53
0.620.71 0.53
0.79
0.56
0.52
0.58
0.66
0.750.71
0.740.69
0.62
0.68
0.63
0.55
0.55
0.65
0.55
0.68
0.740.66
0.68
0.6
0.52
0.69
0.6
0.72
0.830.59
0.910.6
0.74
0.52
0.59
0.71
0.76
0.73
0.54
0.52
0.94
0.52
0.54
0.73
0.53
0.53
0.51
0.5
0.54
0.64
0.62
0.82
0.59
0.71
0.9
0.66
0.51
0.84
0.73
0.51
0.52
0.72
0.59
0.56
0.53
0.61
0.7
0.67
0.52
0.63
0.82
0.53
0.610.550.5
0.93
0.530.55
0.5
0.59
0.52
0.620.52
0.50.56
0.53
0.68
0.56
0.56
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0.5
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0.61
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0.69
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0.65
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0.79
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0.78
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0.77
0.78
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0.76
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0.850.83
0.82
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0.74
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0.69
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0.6
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0.56
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0.6
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0.5
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0.630.53
0.53
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0.55
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0.56
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0.65
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PDP:3N94Ab PDP:3Q27Ab
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PDP:2B3FAb
PDP:3A09Ab
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PDP:3BQPAa
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PDP:2FN9Aa
PDP:3QJGAa
PDP:2VOYIa
PDP:3IPCAb
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PDP:2ZXEAa
PDP:3CSGAb PDP:2VGQAb PDP:3C4MAb
PDP:3IOWAc PDP:3F5FAc PDP:2XZ3Ac
PDP:2FSHAa d1nkta3
PDP:3PEYAa d1t6na_
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PDP:3CIJAa
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PDP:2B3FAa
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PDP:2O1MAb PDP:3G3KAb
PDP:2V25Ab
PDP:3DM5Aa
PDP:2QRYAb
PDP:3U5ERc
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d1w9ea2
PDP:2KJDAa
d1by5a_
PDP:3DDRAa PDP:1XKHAa
d2gufa1PDP:1XKWAa PDP:2O5PAb
PDP:2QX5Ab
PDP:3I33Ad
PDP:2VU9Ab
PDP:2FQXAa PDP:1XEZAc
d1mfqc_
d1qb2a_
PDP:3TEWAa
PDP:2ZS6Bb
PDP:3A1DAb
d2a29a1
PDP:2VOYJa
PDP:2IYEAb
PDP:2JLJAa
PDP:2RPWX_
d1lw7a1
d1orqc_
PDP:3R8SCa
d1mp1a_
d2huga1
PDP:2VOYB_
d1hz3a_d2nvub1
PDP:3FEWXc
PDP:3R8S1a
PDP:3N40Fa
PDP:3B5DAa
d2df7a1
d1fs0e1
d1oxxk1
d2ebfx1
d2vv5a1
d1t1ua2
PDP:3HO6Aa
PDP:3LMAAa
d1diva1
d1gpra_
PDP:3R8SDa
PDP:2QDZAb
d2a7ub1
PDP:3RLFFa
PDP:2QDZAa
d1cw5a_
PDP:3U5ERa
d2ebfx2
PDP:2JPKA_
d1ujla_
PDP:2QP2Ab
PDP:2DPYAc
PDP:3IAM6a
PDP:3KTMAa
d1mwpa_
PDP:3C4MAc d1zyma2PDP:2HROAa
PDP:3B7KAb
PDP:3N94Ac
PDP:3B7KAa
PDP:2PZEAb
PDP:2VU9Aa
d1a8da1 PDP:3KQRAa
PDP:3BG1Bb
PDP:3FEWXd
PDP:3M4YAc
d1a87a_
PDP:2ETBAa
PDP:3EU9Aa
PDP:2J42Ad PDP:3T3LAa
d1ew4a_
PDP:3IAM7a
PDP:3TWRAa
PDP:1YRTAa
PDP:2KRGAa
PDP:2VQGAa
PDP:3IAM5a
PDP:2WW9Af
PDP:3IAM9b
PDP:2NVJA_
PDP:2NOOAb
PDP:2HC8Aa
PDP:2WW9Ad
PDP:3IAM1b
PDP:2ZXEAb
PDP:1WTHAe
PDP:1XEZAd
d1whia_
d1jo6a_PDP:2POHAd
d2a5yb3
d1diva2 d1qoya_PDP:3SS1Ab
PDP:3DP5Aa d1i8oa_
d2jdia1
d2jdid1
PDP:2C61Ab
d2cfqa1
PDP:3CU4Aa
PDP:2NLSAa
PDP:3F3FCc
PDP:2QX5Aa
PDP:3JROAb
PDP:2NQ2Cb
PDP:3IAM3a PDP:3IAM1a
d1ciia1
PDP:2I88Aa
d1rh1a2
PDP:2CBZAb
PDP:2IXEAb PDP:3TUICc