EXPLORING INTERNAL SYMMETRY AND STRUCTURAL REPEATS WITH CE-SYMMSpencer BlivenJuly 8, 20163DSIG. Orlando, FL
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LEVELS OF SYMMETRY: QUATERNARY SYMMETRY DNA Clamps are found
as dimers in bacteria or trimers in eukaryotes
DNA is bound in the central channel
Proliferating Cell Nuclear Antigen [1VYM](DNA modeled from 1BNA)
Stoichiometry: A3Symmetry: C3
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LEVELS OF SYMMETRY: SYMMETRY OF DOMAINS 6 “processivity fold”
domains
Proliferating Cell Nuclear Antigen [1VYM]
Stoichiometry: A6Symmetry: C6
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LEVELS OF SYMMETRY: INTERNAL SYMMETRY
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.
Stoichiometry: A12Symmetry: D6
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SIGNIFICANCE Evolution
Identify duplications & fusions Many examples of homologous quaternary symmetric/internally
symmetric proteins Tradeoff between monomer & oligomer
Ancient protomer (x2?)
x6
Bacterial DimerEukaryotic/Archaeal/Viral Trimer
x2x3
DNA polymerase IIIβ
E. coli[1MMI]
Proliferating Cell Nuclear Antigen
Human[1VYM]
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SIGNIFICANCE
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.
TATA Binding Protein [1TGH]
Hemoglobin[4HHB]
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SIGNIFICANCE
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.
Hemoglobin[4HHB]
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TYPES OF SYMMETRY
Cyclic (C8)TIM barrel
[1TIM]
Dihedral (D2)Glyoxalase
[3B59]
Helical (H3)Antifreeze Protein
[1L0S]
Translational (R)Ankyrin Repeat
[1N0R]
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HIERARCHICAL SYMMETRY
ɣB-Crystallin[4GCR]C2+C2
Vitamin C transporter
[4RP8]C2+C2/Broken D2
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CE-SYMM 2.0
Multiple alignment between all repeats Open and Closed symmetry Multiple Axes and hierarchical symmetry Point Group detection Monte Carlo alignment optimization https://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
Glyoxalase[3B59]
D2
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Monoamine Oxidase Regulatory Protein [1Q6W]
DIFFERENT STOICHIOMETRY, SAME STRUCTURE
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Monoamine Oxidase Regulatory Protein [1Q6W]
DIFFERENT STOICHIOMETRY, SAME STRUCTURE
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Monoamine Oxidase Regulatory Protein [1Q6W]
MaoC domain protein dehydratase [4E3E]
DIFFERENT STOICHIOMETRY, SAME STRUCTURE
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Monoamine Oxidase Regulatory Protein [1Q6W]
MaoC domain protein dehydratase [4E3E]
DIFFERENT STOICHIOMETRY, SAME STRUCTURE
A6 stoichiometryD3 symmetry
A3 stoichiometryC3 symmetry?
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Monoamine Oxidase Regulatory Protein [1Q6W]
MaoC domain protein dehydratase [4E3E]
DIFFERENT STOICHIOMETRY, SAME STRUCTURE
[ND]xxxxH
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PROMINENT IN MEMBRANE PROTEINS Major Facilitator
Superfamily Lactose/Proton symporter Lactose binds at center 4 repeats (2 inverted)
periplasm
cytosol
LacY[1Q6W]
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CE-SYMM 2.0 ALGORITHMStructure
1. Structural Self Alignment
Self-Alignment
TM-Score
2.Order Detection
Order
3. Refinement
Multiple Alignment
4. Optimization
TM-ScoreAsymmetry Symmetry
6. Point Group Detection
5. Iterate
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CE-SYMM 2.0 ALGORITHMStructure
1. Structural Self Alignment
Self-Alignment
TM-Score
2.Order Detection
Order
3. Refinement
Multiple Alignment
4. Optimization
TM-ScoreAsymmetry Symmetry
6. Point Group Detection
5. IterateKeap1 Kelch
domain[1U6D]
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CE-SYMM 2.0 ALGORITHMStructure
1. Structural Self Alignment
Self-Alignment
TM-Score
Order
Multiple Alignment
4. Optimization
TM-ScoreAsymmetry Symmetry
6. Point Group Detection
5. Iterate
3. Refinement
Keap1 Kelch domain[1U6D]
2.Order Detection
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CE-SYMM 2.0 ALGORITHMStructure
1. Structural Self Alignment
Self-Alignment
TM-Score
2.Order Detection
Order
3. Refinement
Multiple Alignment
TM-ScoreAsymmetry Symmetry
6. Point Group Detection
5. Iterate
4. Optimization
Keap1 Kelch domain[1U6D]
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CE-SYMM 2.0 ALGORITHMStructure
1. Structural Self Alignment
Self-Alignment
TM-Score
2.Order Detection
Order
3. Refinement
Multiple Alignment
4. Optimization
TM-ScoreAsymmetry Symmetry
6. Point Group Detection
5. Iterate
Keap1 Kelch domain[1U6D]
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CENSUS All domains from SCOPe 2.06 Underestimate based on conservative thresholds
Order Number of Superfamilies
% symmetric
Asymmetric 1051 75.39%Rotational 302 21.66%
C2 237 78.48%C3 19 6.29%C4 12 3.97%C5 2 0.66%C6 8 2.65%C7 16 5.30%C8 8 2.65%
Dihedral 19 1.36%D2 17 89.47%D3 2 10.53%
Helical 7 0.50%Translationa
l 15 1.08%
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SUMMARY
Nature utilizes symmetry at multiple levels
Internal symmetry can reveal evolutionary history of folds
Duplications & fusions can preserve the overall biological assembly
Internal symmetry is a multiple alignment problem
CE-Symm is able to automatically detect most types of structural repeats
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ACKNOWLEDGEMENTS Paul Scherrer Institute
Guido Capitani Aleix Lafita
UC San Diego/RCSB Douglas Myers-Turnbull Andreas Prlić Peter Rose Jose Duarte RCSB & Bourne Lab
members NIH
Philip Bourne Philippe Youkharibache David Landsman
Resources: github.com/rcsb/symmetry source.rcsb.org/
jfatcatserver/symmetry.jsp www.slideshare.net/sbliven
Funding: NCBI/NLM/NIHRCSB: NSF, NIH, DOE
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RNA INTERNAL SYMMETRY
FMN Riboswitch [3F4E]
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PTSIIA/GUTA-LIKE DOMAIN 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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ABC TRANSPORTER
BtuF
BtuC
BtuD
Vitamin B12 transporter BtuCD–F from E. coli [4FI3]
Periplasmic-binding protein
Transmembrane domain
Nucleotide-binding domain
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ABC TRANSPORTER
BtuF [1N4A]
BtuF
BtuC
BtuD
Vitamin B12 transporter BtuCD–F from E. coli [4FI3]
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BENCHMARK 1007 structures from SCOP
superfamilies Manually curated Excludes small proteins (<4
SSEs) 26% of superfamilies have
internal symmetry or large structural repeats
Order Superfamilies
%
Asymmetric
747 74.2%
Rotational 214 21.2%2 160 74.8%3 10 4.7%4 2 0.9%5 3 1.4%6 9 4.2%7 10 4.7%8 20 9.3%
Dihedral 18 1.8%D2 14 77.8%D3 1 5.6%D4 2 11.1%D5 1 5.6
Helical 11 1.1%H2 9 81.8%H3 2 18.2%
H10 1 9.1%Superhelical
2 0.2%
Translational
15 1.5%
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PERFORMANCE
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PERFORMANCE
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CE-SYMM: SELF-ALIGNMENT
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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CE-SYMM: SELF-ALIGNMENT
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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βγ-CRYSTALLIN FAMILY
Aravind, P., Mishra, A., Suman, S. K., Jobby, M. K., Sankaranarayanan, R., & Sharma, Y. (2009). The betagamma-crystallin superfamily contains a universal motif for binding calcium. Biochemistry, 48(51), 12180–12190.
M-Crystallin[3HZ2.A]
C2
Bovine ɣB-Crystallin[4GCR]C2+C2
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