My talk for the 28th Rhine-Knee Regional Meeting on Biocrystallography

1. Spencer Bliven
September 24-26, 2014
28th Rhine-Knee Regional Meeting on Biocrystallography

2. Hemoglobin
[PDB:4HHB]
C2
Rhinovirus 2
[3DPR]
Icosahedral
GTP
Cyclohydrolase I
[1A8R]
D5
AmtB Ammonia
Channel
[1U7G]
C3
1

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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4.  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.
Hemoglobin
[4HHB]
TATA Binding Protein
3
[1TGH]

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.
4
Hemoglobin
[4HHB]

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
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3OL0 3O49

7. E. Coli DNA polymerase III beta subunit
 2 chains (C2 crystal axis)
Human proliferating cell nuclear
antigen
 3 chains (C3 crystal axis)
1MMI
1VYM
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8. E. Coli DNA polymerase III beta subunit
 2 chains
 6 domains (pseudo C6)
Human proliferating cell nuclear
antigen
 3 chains
 6 domains (pseudo C6)
1MMI
1VYM
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9.  2-3 chains
 6 domains
 12 structural repeats (pseudo D6)
Ancient 12-mer?
Ancient 6-mer
Eukaryotic/Archaeal/V Bacterial Dimer
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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10. 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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11. 10
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)

12.  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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13.  Extends Combinatorial Extension
(CE) algorithm for structural
alignment
 Web server:
source.rcsb.org/jfatcatserver/sym
metry.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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14.  PTS sorbitol transporter subunit IIA
 Novel fold
 Solved by the Protein Structure Initiative
 Structural alignment reveals a conserved sequence motif
between halves
2F9H
13

15.  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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16.  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/sym
metry.jsp
 github.com/rcsb/symmetry
 www.slideshare.net/sbliven
Funding: NSF, NIH, DOE, Open
Science Grid
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18.  racemases and epimerases are enriched
17

19. 18

20. 120° 120°
Fibroblast Growth
Factor [3JUT]
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

21. 120° 120°
Fibroblast Growth
Factor [3JUT]
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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22.  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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23.  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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24. 23
BtuF [1N4A]
BtuF
BtuC
BtuD
Vitamin B12 transporter BtuCD–F from E. coli [4FI3]

25. This work is licensed under a
Creative Commons Attribution-ShareAlike 3.0 Unported License.
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