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Spencer Bliven 
September 24-26, 2014 
28th Rhine-Knee Regional Meeting on Biocrystallography
Hemoglobin 
[PDB:4HHB] 
C2 
Rhinovirus 2 
[3DPR] 
Icosahedral 
GTP 
Cyclohydrolase I 
[1A8R] 
D5 
AmtB Ammonia 
Channel 
[...
Ferredoxin-like 
[SCOP:d2j5aa1] 
C2 
Beta-Propeller 
[SCOP:d1u6dx_] 
C6 
Beta-trefoil 
[3JUT] 
C3 
TIM barrel 
[1TIM] 
C8 ...
 Function 
 Allosteric regulation/cooperativity 
 Bind ligands symmetrically (e.g. 
metals, palindromic DNA, channels) ...
 Function 
 Allosteric regulation/cooperativity 
 Bind ligands symmetrically (e.g. 
metals, palindromic DNA, channels) ...
 Evolution 
 Identify duplications & fusions 
 Many examples of homologous quaternary 
symmetric/internally symmetric p...
E. Coli DNA polymerase III beta subunit 
 2 chains (C2 crystal axis) 
Human proliferating cell nuclear 
antigen 
 3 chai...
E. Coli DNA polymerase III beta subunit 
 2 chains 
 6 domains (pseudo C6) 
Human proliferating cell nuclear 
antigen 
...
 2-3 chains 
 6 domains 
 12 structural repeats (pseudo D6) 
Ancient 12-mer? 
Ancient 6-mer 
Eukaryotic/Archaeal/V Bact...
Glyoxalase I from 
Clostridium 
acetobutylicum [3HDP] 
(Nickel; Dimer) 
Glyoxalase I from E. 
coli [1F9Z] 
(Nickel; Dimer)...
10 
Glyoxalase I from 
Clostridium 
acetobutylicum [3HDP] 
(Nickel; Dimer) 
Glyoxalase I from E. 
coli [1F9Z] 
(Nickel; Di...
 1007 structures from 
SCOP superfamilies 
 Manually curated 
 Excludes small proteins 
(<4 SSEs) 
 24% of superfamili...
 Extends Combinatorial Extension 
(CE) algorithm for structural 
alignment 
 Web server: 
source.rcsb.org/jfatcatserver/...
 PTS sorbitol transporter subunit IIA 
 Novel fold 
 Solved by the Protein Structure Initiative 
 Structural alignment...
 24% of domains have internal symmetry 
 Symmetry gives clues about duplication events 
 Symmetry is deeply tied to pro...
 Paul Scherrer Institute 
 Guido Capitani 
 Kumaran Baskaran 
 Jose Duarte 
 Joseph Somody 
 UC San Diego/RCSB 
 Do...
 racemases and epimerases are enriched 
17
18
120° 120° 
Fibroblast Growth 
Factor [3JUT] 
Myers-Turnbull, D., Bliven, S. E., Rose, P. W., Aziz, Z. K., Youkharibache, P...
120° 120° 
Fibroblast Growth 
Factor [3JUT] 
Myers-Turnbull, D., Bliven, S. E., Rose, P. W., Aziz, Z. K., Youkharibache, P...
 AUC = .95 
 86% True Positive 
Rate 
 3.3% False Positive 
Rate 
SymD: 
Kim, C., Basner, J., & Lee, B. (2010). BMC 
Bi...
 All domains from SCOPe 2.03 
 Interactive results: 
source.rcsb.org/jfatcatserver/scopResults.jsp 
 Underestimate base...
23 
BtuF [1N4A] 
BtuF 
BtuC 
BtuD 
Vitamin B12 transporter BtuCD–F from E. coli [4FI3]
This work is licensed under a 
Creative Commons Attribution-ShareAlike 3.0 Unported License. 
24
Systematic detection of internal symmetry in proteins - Rheinknie Regiomeeting 2014
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Systematic detection of internal symmetry in proteins - Rheinknie Regiomeeting 2014

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Systematic detection of internal symmetry in proteins - Rheinknie Regiomeeting 2014

  1. 1. Spencer Bliven September 24-26, 2014 28th Rhine-Knee Regional Meeting on Biocrystallography
  2. 2. Hemoglobin [PDB:4HHB] C2 Rhinovirus 2 [3DPR] Icosahedral GTP Cyclohydrolase I [1A8R] D5 AmtB Ammonia Channel [1U7G] C3 1
  3. 3. Ferredoxin-like [SCOP:d2j5aa1] C2 Beta-Propeller [SCOP:d1u6dx_] C6 Beta-trefoil [3JUT] C3 TIM barrel [1TIM] C8 Key: Crystallographic/NCS axis Pseudosymmetry axis 2
  4. 4.  Function  Allosteric regulation/cooperativity  Bind ligands symmetrically (e.g. metals, palindromic DNA, channels) Monod, J., Wyman, J., & Changeux, J.-P. (1965). J Mol Biol, 12, 88–118. Hemoglobin [4HHB] TATA Binding Protein 3 [1TGH]
  5. 5.  Function  Allosteric regulation/cooperativity  Bind ligands symmetrically (e.g. metals, palindromic DNA, channels)  Folding  Prevent infinite assembly  Subunits fold quasi-independently TATA Binding Protein [1TGH] Monod, J., Wyman, J., & Changeux, J.-P. (1965). J Mol Biol, 12, 88–118. Wolynes, P. G. (1996). PNAS, 93(25), 14249–14255. 4 Hemoglobin [4HHB]
  6. 6.  Evolution  Identify duplications & fusions  Many examples of homologous quaternary symmetric/internally symmetric proteins  Tradeoff between monomer & oligomer Lee and Blaber. PNAS (2011) vol. 108 (1) pp. 126-30 5 3OL0 3O49
  7. 7. E. Coli DNA polymerase III beta subunit  2 chains (C2 crystal axis) Human proliferating cell nuclear antigen  3 chains (C3 crystal axis) 1MMI 1VYM 6
  8. 8. E. Coli DNA polymerase III beta subunit  2 chains  6 domains (pseudo C6) Human proliferating cell nuclear antigen  3 chains  6 domains (pseudo C6) 1MMI 1VYM 7
  9. 9.  2-3 chains  6 domains  12 structural repeats (pseudo D6) Ancient 12-mer? Ancient 6-mer Eukaryotic/Archaeal/V Bacterial Dimer iral Trimer Kelman, Z., & O'Donnell, M. (1995). Nucleic Acids Research, 23(18), 3613–3620. Neuwald, A. F., & Poleksic, A. (2000). Nucleic Acids Research, 28(18), 3570–3580. 8
  10. 10. Glyoxalase I from Clostridium acetobutylicum [3HDP] (Nickel; Dimer) Glyoxalase I from E. coli [1F9Z] (Nickel; Dimer) 1,2-dihydroxy-naphthalene dioxygenase from Pseudomonas sp. strain C18 [2EHZ] (Iron; Octamer) 9
  11. 11. 10 Glyoxalase I from Clostridium acetobutylicum [3HDP] (Nickel; Dimer) Glyoxalase I from E. coli [1F9Z] (Nickel; Dimer) 1,2-dihydroxy-naphthalene dioxygenase from Pseudomonas sp. strain C18 [2EHZ] (Iron; Octamer)
  12. 12.  1007 structures from SCOP superfamilies  Manually curated  Excludes small proteins (<4 SSEs)  24% of superfamilies have internal symmetry or large structural repeats Order Superfamilies % Asymmetric 766 76.10% Rotational 2 166 16.5% 3 10 1.0% 4 2 0.2% 5 3 0.3% 6 9 0.9% 7 9 0.9% 8 21 2.1% Dihedral 2 2 0.2% 4 1 0.1% Helical 2 9 0.9% 3 2 0.2% Non-integral 2 0.2% Superhelical 2 0.2% Translational 3 0.3% 11
  13. 13.  Extends Combinatorial Extension (CE) algorithm for structural alignment  Web server: source.rcsb.org/jfatcatserver/sym metry.jsp  Download & Source code: github.com/rcsb/symmetry (LGPL)  Myers-Turnbull, D., Bliven, S. E., Rose, P. W., Aziz, Z. K., Youkharibache, P., Bourne, P. E., & Prlić, A. (2014). Systematic Detection of Internal Symmetry in Proteins Using CE-Symm. Journal of Molecular Biology, 426(11), 2255–2268. 12
  14. 14.  PTS sorbitol transporter subunit IIA  Novel fold  Solved by the Protein Structure Initiative  Structural alignment reveals a conserved sequence motif between halves 2F9H 13
  15. 15.  24% of domains have internal symmetry  Symmetry gives clues about duplication events  Symmetry is deeply tied to protein function  CE-Symm can accurately detect internal symmetry SCOP:d1su3a2 d1pt2a_ d1c5ka1 d1k3ia3 d1h9ya2 14
  16. 16.  Paul Scherrer Institute  Guido Capitani  Kumaran Baskaran  Jose Duarte  Joseph Somody  UC San Diego/RCSB  Douglas Myers-Turnbull  Andreas Prlić  Peter Rose  Zaid Aziz  RCSB & Bourne Lab members  NIH  Philip Bourne  Philippe Youkharibache  David Landsman Resources:  source.rcsb.org/jfatcatserver/sym metry.jsp  github.com/rcsb/symmetry  www.slideshare.net/sbliven Funding: NSF, NIH, DOE, Open Science Grid 15
  17. 17.  racemases and epimerases are enriched 17
  18. 18. 18
  19. 19. 120° 120° Fibroblast Growth Factor [3JUT] Myers-Turnbull, D., Bliven, S. E., Rose, P. W., Aziz, Z. K., Youkharibache, P., Bourne, P. E., & Prlić, A. (2014). Journal of Molecular Biology, 426(11), 2255–2268. 19
  20. 20. 120° 120° Fibroblast Growth Factor [3JUT] Myers-Turnbull, D., Bliven, S. E., Rose, P. W., Aziz, Z. K., Youkharibache, P., Bourne, P. E., & Prlić, A. (2014). Journal of Molecular Biology, 426(11), 2255–2268. 20
  21. 21.  AUC = .95  86% True Positive Rate  3.3% False Positive Rate SymD: Kim, C., Basner, J., & Lee, B. (2010). BMC Bioinformatics, 11, 303. 21
  22. 22.  All domains from SCOPe 2.03  Interactive results: source.rcsb.org/jfatcatserver/scopResults.jsp  Underestimate based on conservative thresholds SCOP Class Superfamilies % Symmetric α 507 18.5% β 354 24.6% α/β 244 16.8% α+β 551 14.3% Multi-domain 66 4.5% Membrane 109 23.8% Overall 1831 18.0% 22
  23. 23. 23 BtuF [1N4A] BtuF BtuC BtuD Vitamin B12 transporter BtuCD–F from E. coli [4FI3]
  24. 24. This work is licensed under a Creative Commons Attribution-ShareAlike 3.0 Unported License. 24

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