Slides from my talk describing CE-Symm and my research on internal symmetry. It was given for jLBR, the weekly seminar series for our department at PSI.

1. Spencer Bliven
September 30, 2014
jLBR Seminar

2. 1
From Google Earth. Data SIO, NOAA, U.S. Navy, NGA,
GEBCO, Image Landsat, Image IBCAO

3. d2hmva1
2
PDP:PDP:d2r4qa1
PDP:3A1DAa
d1djla_
PDP:2VOYIa
d1shux_
d1d4oa_
! What’s the nature of protein fold space?
! How do new folds evolve?
d1nrjb_
! 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?
PDP:2IYEAa
PDP:3QJGAa
PDP:2FN9Aa
d1wa5a_
PDP:3QELBa
PDP:3RBZAb
d1id1a_
PDP:2WI8Aa
PDP:3IPCAa
d1ls1a2
SCOP:d1su3a2 d1pt2a_ d1c5ka1 d1k3ia3 d1h9ya2

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

5. Ferredoxin-like
[SCOP:d2j5aa1]
C2
Beta-Propeller
[SCOP:d1u6dx_]
C6
Beta-trefoil
[3JUT]
C3
TIM barrel
[1TIM]
C8
Key: Crystallographic/NCS axis Pseudosymmetry axis
4

6. ! 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
5
[1TGH]

7. ! 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.
6
Hemoglobin
[4HHB]

8. ! 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
7
3OL0 3O49

9. E. Coli DNA polymerase III beta
subunit
! 2 chains (C2 crystal axis)
Human proliferating cell nuclear
antigen
! 3 chains (C3 crystal axis)
1MMI
1VYM
8

10. 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
9

11. ! 2-3 chains
! 6 domains
! 12 structural repeats (pseudo D6)
Ancient 12-mer?
Ancient 6-mer
Eukaryotic/Archaeal/ Bacterial Dimer
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.
10

12. 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)
11

13. 12
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)

14. ! 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.
13

15. 14
PDB:1MER Chain A

16. ! 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%
15

17. ! AUC = .95
! 86% True Positive
Rate
! 3.3% False
Positive Rate
SymD:
Kim, C., Basner, J., & Lee, B. (2010). BMC
Bioinformatics, 11, 303.
16

18. ! 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%
17

19. Periplasmic-binding protein
Nucleotide-binding domain
18
BtuF
BtuC
BtuD
Transmembrane domain
Vitamin B12 transporter BtuCD–F from E. coli [4FI3]

20. 19
BtuF
BtuC
BtuD
Vitamin B12 transporter BtuCD–F from E. coli [4FI3]

21. 20
BtuF [1N4A]
BtuF
BtuC
BtuD
Vitamin B12 transporter BtuCD–F from E. coli [4FI3]

22. ! PTS sorbitol transporter subunit IIA
! Novel fold
! Solved by the Protein Structure Initiative
! Structural alignment reveals a conserved sequence
motif between halves
2F9H
21

23. 22
! 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

24. ! 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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26. ! Racemases and epimerases are enriched
25

27. 4
3
2
1
0
0.00 0.25 0.50 0.75
TM−Score
Density
Asymmetric
Symmetric
26

28. 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.
27

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