Spencer Bliven September 30, 2014

jLBR Seminar

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From Google Earth. Data SIO, NOAA, U.S. Navy, NGA, GEBCO, Image Landsat, Image IBCAO

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PDP:2AEFAa PDP:3IPRAa

PDP:2FN9Ab

d1iiba_

d2r4qa1

PDP:3L9WAa

d1pdoa_

PDP:3A1DAa

d1djla_d1shux_

d1d4oa_

d1nrjb_

PDP:2IYEAa

PDP:2FN9Aa

PDP:2ZXEAa

PDP:2VOYIa

d1wa5a_

PDP:3QELBa

PDP:3QELBb

PDP:2O1EAb

d1nrza_

PDP:2OSVAa

PDP:2OSVAb

PDP:3HH8Aa

PDP:2O1EAa

PDP:3HH8Ab

PDP:3IPCAb

PDP:2Q8PAa

d1id1a_

d2hmva1

PDP:2WI8Aa

PDP:3QJGAa

PDP:3P2YAb

d1ls1a2

PDP:2FEWBa

PDP:3RBZAb

d1vkra_PDP:2VQ3Aa

PDP:3IPCAa

SCOP:d1su3a2 d1pt2a_ d1c5ka1 d1k3ia3 d1h9ya2

!  What’s the nature of protein fold space? !  How do new folds evolve? !  How do gene rearrangements relate to protein

structure? !  What can internal symmetry tell us about protein

function and evolution? !  What algorithms are best for detecting remote

homology?

Hemoglobin [PDB:4HHB]

C2

GTP Cyclohydrolase I

[1A8R] D5

Rhinovirus 2 [3DPR]

Icosahedral

AmtB Ammonia Channel [1U7G]

C3

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

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!  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.

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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)

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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 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.

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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)

!  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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PDB:1MER Chain A

!  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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! 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% Membrane 109 23.8% Overall 1831 18.0%

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BtuF

BtuC

BtuD

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

Periplasmic-binding protein

Transmembrane domain

Nucleotide-binding domain

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BtuF

BtuC

BtuD

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

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BtuF [1N4A]

BtuF

BtuC

BtuD

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

!  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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!  Systematically compare symmetry units across the PDB

!  CE-Symm improvements !  Improve order detection

(C8, not C4 or C2)

!  Visualization & usability

!  Find mixed quaternary & internal symmetry

!  Paul Scherrer Institute !  Guido Capitani !  Kumaran Baskaran !  Jose Duarte !  Joseph Somody !  LBR members

!  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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0

1

2

3

4

0.00 0.25 0.50 0.75TM−Score

Density

AsymmetricSymmetric

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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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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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