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3DSIG 2016 Presentation: Exploring Internal Symmetry and Structural Repeats with CE-Symm

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Understanding the role and evolution of internal symmetry in protein structure is a fundamental question in structural biology. We present here CE-Symm 2.0, a key tool to address that question, which is able to detect all types of protein internal symmetry and provides a robust and intuitive sequence-to-structure analysis of all repeats. Notable features compared to the previous version include an optimized multiple alignment between repeats, determination of the full point group, and identification of multiple symmetry axes. We expect CE-Symm to find ample use in evolutionary studies, functional annotation, and structural classification of proteins.

This work was presented at the 3DSIG 2016 conference in Orlando, FL, on July 8, 2016.

See also the poster form: http://www.slideshare.net/sbliven/3dsig-2016-poster-exploring-internal-symmetry-and-structural-repeats-with-cesymm

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3DSIG 2016 Presentation: Exploring Internal Symmetry and Structural Repeats with CE-Symm

  1. 1. EXPLORING INTERNAL SYMMETRY AND STRUCTURAL REPEATS WITH CE-SYMM Spencer Bliven July 8, 2016 3DSIG. Orlando, FL
  2. 2. 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: A3 Symmetry: C3 1
  3. 3. LEVELS OF SYMMETRY: SYMMETRY OF DOMAINS  6 “processivity fold” domains Proliferating Cell Nuclear Antigen [1VYM] Stoichiometry: A6 Symmetry: C6 2
  4. 4. 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: A12 Symmetry: D6 3
  5. 5. SIGNIFICANCE  Evolution  Identify duplications & fusions  Many examples of homologous quaternary symmetric/internally symmetric proteins  Tradeoff between monomer & oligomer 4 Ancient protomer (x2?) x6 Bacterial DimerEukaryotic/Archaeal/Viral Trimer x2x3 DNA polymerase IIIβ E. coli [1MMI] Proliferating Cell Nuclear Antigen Human [1VYM]
  6. 6. 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] 5
  7. 7. 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] 6
  8. 8. TYPES OF SYMMETRY Cyclic (C8) TIM barrel [1TIM] Dihedral (D2) Glyoxalase [3B59] Helical (H3) Antifreeze Protein [1L0S] Translational (R) Ankyrin Repeat [1N0R] 7
  9. 9. HIERARCHICAL SYMMETRY ɣB-Crystallin [4GCR] C2+C2 Vitamin C transporter [4RP8] C2+C2/Broken D2 8
  10. 10. 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 9
  11. 11. Monoamine Oxidase Regulatory Protein [1Q6W] DIFFERENT STOICHIOMETRY, SAME STRUCTURE 10
  12. 12. Monoamine Oxidase Regulatory Protein [1Q6W] DIFFERENT STOICHIOMETRY, SAME STRUCTURE 11
  13. 13. Monoamine Oxidase Regulatory Protein [1Q6W] MaoC domain protein dehydratase [4E3E] DIFFERENT STOICHIOMETRY, SAME STRUCTURE 12
  14. 14. Monoamine Oxidase Regulatory Protein [1Q6W] MaoC domain protein dehydratase [4E3E] DIFFERENT STOICHIOMETRY, SAME STRUCTURE 13 A6 stoichiometry D3 symmetry A3 stoichiometry C3 symmetry?
  15. 15. Monoamine Oxidase Regulatory Protein [1Q6W] MaoC domain protein dehydratase [4E3E] DIFFERENT STOICHIOMETRY, SAME STRUCTURE 14 [ND]xxxxH
  16. 16. PROMINENT IN MEMBRANE PROTEINS  Major Facilitator Superfamily  Lactose/Proton symporter  Lactose binds at center  4 repeats (2 inverted) periplasm cytosol 15 LacY [1Q6W]
  17. 17. CE-SYMM 2.0 ALGORITHM Structure 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 16
  18. 18. CE-SYMM 2.0 ALGORITHM Structure 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] 17
  19. 19. CE-SYMM 2.0 ALGORITHM Structure 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] 18 2.Order Detection
  20. 20. CE-SYMM 2.0 ALGORITHM Structure 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] 19
  21. 21. CE-SYMM 2.0 ALGORITHM Structure 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] 20
  22. 22. CENSUS  All domains from SCOPe 2.06  Underestimate based on conservative thresholds 21 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% Translational 15 1.08%
  23. 23. 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 22
  24. 24. 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/sy mmetry.jsp  www.slideshare.net/sbliven Funding: NCBI/NLM/NIH RCSB: NSF, NIH, DOE 23
  25. 25. 24
  26. 26. RNA INTERNAL SYMMETRY FMN Riboswitch [3F4E] 25
  27. 27. 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 26
  28. 28. ABC TRANSPORTER BtuF BtuC BtuD Vitamin B12 transporter BtuCD–F from E. coli [4FI3] Periplasmic-binding protein Transmembrane domain Nucleotide-binding domain 27
  29. 29. ABC TRANSPORTER BtuF [1N4A] BtuF BtuC BtuD Vitamin B12 transporter BtuCD–F from E. coli [4FI3] 28
  30. 30. 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% 29
  31. 31. PERFORMANCE 30
  32. 32. PERFORMANCE 31
  33. 33. 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. 32
  34. 34. 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. 33
  35. 35. βγ-CRYSTALLIN FAMILY 34 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
  36. 36. This work is licensed under a Creative Commons Attribution-ShareAlike 3.0 Unported License. 35

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