Spencer Bliven

September 24-26, 2014

28th Rhine-Knee Regional Meeting on Biocrystallography

Hemoglobin

[PDB:4HHB]

C2

GTP

Cyclohydrolase I

[1A8R]

D5

Rhinovirus 2

[3DPR]

Icosahedral

AmtB Ammonia

Channel

[1U7G]

C3

1

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

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.

3

TATA Binding Protein

[1TGH]

Hemoglobin

[4HHB]

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.

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Hemoglobin

[4HHB]

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

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3OL0 3O49

E. Coli DNA polymerase III beta subunit

2 chains (C2 crystal axis)

Human proliferating cell nuclear antigen

3 chains (C3 crystal axis)

6

1MMI

1VYM

E. Coli DNA polymerase III beta subunit

2 chains

6 domains (pseudo C6)

Human proliferating cell nuclear antigen

3 chains

6 domains (pseudo C6)

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1MMI

1VYM

2-3 chains

6 domains

12 structural repeats (pseudo D6)

Ancient 12-mer?

Ancient 6-mer

Bacterial DimerEukaryotic/Archaeal/V

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.

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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)

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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)

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%

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Extends Combinatorial Extension (CE) algorithm for structural alignment

Web server: source.rcsb.org/jfatcatserver/symmetry.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.

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PTS sorbitol transporter subunit IIA

Novel fold

Solved by the Protein Structure Initiative

Structural alignment reveals a conserved sequence motif between halves

2F9H

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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

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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/symmetry.jsp

github.com/rcsb/symmetry

www.slideshare.net/sbliven

Funding: NSF, NIH, DOE, Open Science Grid

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racemases and epimerases are enriched

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18

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.

19

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.

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AUC = .95

86% True Positive Rate

3.3% False Positive Rate

SymD:

Kim, C., Basner, J., & Lee, B. (2010). BMC

Bioinformatics, 11, 303.

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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%

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BtuF [1N4A]

BtuF

BtuC

BtuD

Vitamin B12 transporter BtuCD–F from E. coli [4FI3]

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Creative Commons Attribution-ShareAlike 3.0 Unported License.

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