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
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/NCS axis Pseudosymmetry axis
! 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.
! 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]
! 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
E. Coli DNA polymerase III beta subunit [1mmi] ! 2 chains (C2 crystal axis)
Human proliferating cell nuclear antigen [1VYM] ! 3 chains (C3 crystal axis)
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)
! 2-3 chains ! 6 domains ! 12 structural repeats (pseudo D6)
Ancient 12-mer?
Ancient 6-mer
Bacterial Dimer Eukaryotic/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.
! 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.
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.
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.
! 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%
! AUC = .95 ! 86% True Positive
Rate ! 3.3% False
Positive Rate
SymD: Kim, C., Basner, J., & Lee, B. (2010). BMC Bioinformatics, 11, 303.
! 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%
! PTS sorbitol transporter subunit IIA ! Novel fold ! Solved by the Protein Structure Initiative ! Structural alignment reveals a conserved sequence
motif between halves
[2F9H]
! 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
! 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
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)
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)
! racemases and epimerases are enriched
0
1
2
3
4
0.00 0.25 0.50 0.75TM−Score
Density
AsymmetricSymmetric
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