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Spencer Bliven
July 11, 2014
3DSIG 2014
Myers-Turnbull, D., Bliven, S. E., Rose, P. W., Aziz, Z. K., Youkharibache, P., Bo...
Hemoglobin [4HHB]
C2
GTP Cyclohydrolase I
[1A8R]
D5
Rhinovirus 2 [3DPR]
Icosahedral
AmtB Ammonia
Channel [1U7G]
C3
Ferredoxin-like
[d2j5aa1]
C2
Beta-Propeller
[d1u6dx_]
C6
Beta-trefoil
[3JUT]
C3
TIM barrel
[1TIM]
C8
Key: Crystallographic...
!  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 ...
E. Coli DNA polymerase III beta
subunit [1mmi]
!  2 chains (C2 crystal axis)
Human proliferating cell nuclear
antigen [1VY...
E. Coli DNA polymerase III beta
subunit [1mmi]
!  2 chains
!  6 domains (pseudo C6)
Human proliferating cell nuclear
antig...
!  2-3 chains
!  6 domains
!  12 structural repeats (pseudo D6)
Ancient 12-mer?
Ancient 6-mer
Bacterial DimerEukaryotic/Ar...
!  Extends Combinatorial
Extension (CE) algorithm
for structural alignment
!  Web server:
source.rcsb.org/
jfatcatserver/s...
Fibroblast Growth
Factor [3JUT]
120° 120°
Myers-Turnbull, D., Bliven, S. E., Rose, P. W., Aziz, Z. K., Youkharibache, P., ...
Fibroblast Growth
Factor [3JUT]
120° 120°
Myers-Turnbull, D., Bliven, S. E., Rose, P. W., Aziz, Z. K., Youkharibache, P., ...
!  1007 structures from
SCOP superfamilies
!  Manually curated
!  Excludes small proteins
(<4 SSEs)
!  24% of superfamilie...
!  AUC = .95
!  86% True Positive
Rate
!  3.3% False
Positive Rate
SymD:
Kim, C., Basner, J., & Lee, B. (2010). BMC
Bioinf...
!  All domains from SCOPe 2.03
!  Interactive results:
source.rcsb.org/jfatcatserver/scopResults.jsp
!  Underestimate base...
!  PTS sorbitol transporter subunit IIA
!  Novel fold
!  Solved by the Protein Structure Initiative
!  Structural alignmen...
!  18-24% of domains have internal symmetry
!  Symmetry gives clues about duplication events
!  Symmetry is deeply tied to...
!  UC San Diego/RCSB
!  Douglas Myers-Turnbull
!  Andreas Prlić
!  Peter Rose
!  Zaid Aziz
!  Milton Saier
!  RCSB & Bourn...
Glyoxalase I from
Clostridium
acetobutylicum [3HDP]
(Nickel; Dimer)
Glyoxalase I from E.
coli [1F9Z]
(Nickel; Dimer)
1,2-d...
Glyoxalase I from
Clostridium
acetobutylicum [3HDP]
(Nickel; Dimer)
Glyoxalase I from E.
coli [1F9Z]
(Nickel; Dimer)
1,2-d...
!  racemases and epimerases are enriched
0
1
2
3
4
0.00 0.25 0.50 0.75
TM−Score
Density
Asymmetric
Symmetric
This work is licensed under a
Creative Commons Attribution-ShareAlike 3.0 Unported License.
3DSIG 2014 Presentation: Systematic detection of internal symmetry in proteins
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3DSIG 2014 Presentation: Systematic detection of internal symmetry in proteins

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These slides are from 3DSIG 2014, presented on July 11.

I describe our investigation of internal symmetry in protein structures. This is quite common (24% of domains), and has many implications for function, folding, and evolution.

I introduce the CE-Symm method, described in

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. doi:10.1016/j.jmb.2014.03.010

I discuss the results from running CE-Symm across the PDB, as well as some particularly compelling examples.

See also my poster by the same title for more details.

Veröffentlicht in: Wissenschaft, Technologie
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3DSIG 2014 Presentation: Systematic detection of internal symmetry in proteins

  1. 1. Spencer Bliven July 11, 2014 3DSIG 2014 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. PMID 24681267
  2. 2. Hemoglobin [4HHB] C2 GTP Cyclohydrolase I [1A8R] D5 Rhinovirus 2 [3DPR] Icosahedral AmtB Ammonia Channel [1U7G] C3
  3. 3. Ferredoxin-like [d2j5aa1] C2 Beta-Propeller [d1u6dx_] C6 Beta-trefoil [3JUT] C3 TIM barrel [1TIM] C8 Key: Crystallographic/NCS axis Pseudosymmetry axis
  4. 4. !  Function !  Allosteric regulation/cooperativity !  Bind ligands symmetrically (e.g. metals, palindromic DNA, channels) TATA Binding Protein [1TGH] Monod, J., Wyman, J., & Changeux, J.-P. (1965). J Mol Biol, 12, 88–118.
  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. Crystal of Squalene synthase [3WCG]
  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
  7. 7. E. Coli DNA polymerase III beta subunit [1mmi] !  2 chains (C2 crystal axis) Human proliferating cell nuclear antigen [1VYM] !  3 chains (C3 crystal axis)
  8. 8. E. Coli DNA polymerase III beta subunit [1mmi] !  2 chains !  6 domains (pseudo C6) Human proliferating cell nuclear antigen [1VYM] !  3 chains !  6 domains (pseudo C6)
  9. 9. !  2-3 chains !  6 domains !  12 structural repeats (pseudo D6) Ancient 12-mer? Ancient 6-mer Bacterial DimerEukaryotic/Archaeal/ Viral 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.
  10. 10. !  Extends Combinatorial Extension (CE) algorithm for structural alignment !  Web server: source.rcsb.org/ jfatcatserver/symmetry.jsp !  Download & Source code: github.com/rcsb/symmetry (LGPL) Shindyalov, I. N., & Bourne, P. E. (1998). Protein Engineering, 11(9), 739–747. Jia, Y., Dewey, T. G., Shindyalov, I. N., & Bourne, P. E. (2004). J Comput Biol, 11(5), 787–799.
  11. 11. Fibroblast Growth Factor [3JUT] 120° 120° 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.
  12. 12. Fibroblast Growth Factor [3JUT] 120° 120° 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.
  13. 13. !  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%
  14. 14. !  AUC = .95 !  86% True Positive Rate !  3.3% False Positive Rate SymD: Kim, C., Basner, J., & Lee, B. (2010). BMC Bioinformatics, 11, 303.
  15. 15. !  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%
  16. 16. !  PTS sorbitol transporter subunit IIA !  Novel fold !  Solved by the Protein Structure Initiative !  Structural alignment reveals a conserved sequence motif between halves [2F9H]
  17. 17. !  18-24% 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 d1su3a2 D1pt2a_ d1c5ka1 d1k3ia3 d1h9ya2
  18. 18. !  UC San Diego/RCSB !  Douglas Myers-Turnbull !  Andreas Prlić !  Peter Rose !  Zaid Aziz !  Milton Saier !  RCSB & Bourne Lab members !  NIH !  Philip Bourne !  Philippe Youkharibache !  David Landsman !  Paul Scherrer Institute !  Guido Capitani & Lab members Resources: !  source.rcsb.org/jfatcatserver/ symmetry.jsp !  github.com/rcsb/symmetry !  Poster 25 !  www.slideshare.net/sbliven !  Funding: NSF, NIH, DOE, Open Science Grid
  19. 19. 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)
  20. 20. 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)
  21. 21. !  racemases and epimerases are enriched
  22. 22. 0 1 2 3 4 0.00 0.25 0.50 0.75 TM−Score Density Asymmetric Symmetric
  23. 23. This work is licensed under a Creative Commons Attribution-ShareAlike 3.0 Unported License.

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