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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., 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
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3DSIG 2014 Poster: Systematic detection of internal symmetry in proteins

Aug 23, 2014

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Spencer Bliven

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.
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Page 1: 3DSIG 2014 Poster: Systematic detection of internal symmetry in proteins

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

Page 2: 3DSIG 2014 Poster: Systematic detection of internal symmetry in proteins

Hemoglobin [4HHB] C2

GTP Cyclohydrolase I [1A8R]

D5

Rhinovirus 2 [3DPR] Icosahedral

AmtB Ammonia Channel [1U7G]

C3

Page 3: 3DSIG 2014 Poster: Systematic detection of internal symmetry in proteins

Ferredoxin-like [d2j5aa1]

C2

Beta-Propeller [d1u6dx_]

C6

Beta-trefoil [3JUT]

C3

TIM barrel [1TIM]

C8

Key: Crystallographic/NCS axis Pseudosymmetry axis

Page 4: 3DSIG 2014 Poster: Systematic detection of internal symmetry in proteins

!  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.

Page 5: 3DSIG 2014 Poster: Systematic detection of internal symmetry in proteins

!  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]

Page 6: 3DSIG 2014 Poster: Systematic detection of internal symmetry in proteins

!  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

Page 7: 3DSIG 2014 Poster: Systematic detection of internal symmetry in proteins

E. Coli DNA polymerase III beta subunit [1mmi] !  2 chains (C2 crystal axis)

Human proliferating cell nuclear antigen [1VYM] !  3 chains (C3 crystal axis)

Page 8: 3DSIG 2014 Poster: Systematic detection of internal symmetry in proteins

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)

Page 9: 3DSIG 2014 Poster: Systematic detection of internal symmetry in proteins

!  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.

Page 10: 3DSIG 2014 Poster: Systematic detection of internal symmetry in proteins

!  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.

Page 11: 3DSIG 2014 Poster: Systematic detection of internal symmetry in proteins

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.

Page 12: 3DSIG 2014 Poster: Systematic detection of internal symmetry in proteins

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.

Page 13: 3DSIG 2014 Poster: Systematic detection of internal symmetry in proteins

!  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%

Page 14: 3DSIG 2014 Poster: Systematic detection of internal symmetry in proteins

! AUC = .95 !  86% True Positive

Rate !  3.3% False

Positive Rate

SymD: Kim, C., Basner, J., & Lee, B. (2010). BMC Bioinformatics, 11, 303.

Page 15: 3DSIG 2014 Poster: Systematic detection of internal symmetry in proteins

!  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%

Page 16: 3DSIG 2014 Poster: Systematic detection of internal symmetry in proteins

!  PTS sorbitol transporter subunit IIA !  Novel fold !  Solved by the Protein Structure Initiative !  Structural alignment reveals a conserved sequence

motif between halves

[2F9H]

Page 17: 3DSIG 2014 Poster: Systematic detection of internal symmetry in proteins

!  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

Page 18: 3DSIG 2014 Poster: Systematic detection of internal symmetry in proteins

!  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

Page 19: 3DSIG 2014 Poster: Systematic detection of internal symmetry in proteins
Page 20: 3DSIG 2014 Poster: Systematic detection of internal symmetry in proteins

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)

Page 21: 3DSIG 2014 Poster: Systematic detection of internal symmetry in proteins

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)

Page 22: 3DSIG 2014 Poster: Systematic detection of internal symmetry in proteins

!  racemases and epimerases are enriched

Page 23: 3DSIG 2014 Poster: Systematic detection of internal symmetry in proteins

0

1

2

3

4

0.00 0.25 0.50 0.75TM−Score

Density

AsymmetricSymmetric

Page 24: 3DSIG 2014 Poster: Systematic detection of internal symmetry in proteins

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