On Symmetry and Pseudo-symmetry in proteins Ismb lbr06 prlic

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My ISMB talk ( #lbr06) - about internal pseudo-symmetry in proteins


  • 1.Internal pseudo- symmetry in proteins Andreas Prli, Spencer E Bliven, Peter Rose, PhilippeYoukharibache, Douglas Myers-Turnbull, Phil E BourneSunday, July 15, 12

2. source: www.rcsb.orgSunday, July 15, 12 3. Biol. Assemblies in PDB1 Bio.parts of a Bio.multiple Bio. One asym unit2hhb 1hho 1h4v Bio. Assembly assigned by Author calculation (PQS, PISA* and curation)* E. Krissinel and K. Henrick, J. Mol. Biol. 2007Sunday, July 15, 12 4. Biol. Assemb. & Disease SNP:rs28940893 causes Metachromatic leukodystrophy (lysosomal storage disorder) asym unit... the exchange of leucine for proline at position 426 increases the susceptibility ofarylsulfatase A to lysosomal cysteine proteinases and results in a severe reduction inthe half-life of the mutant polypeptidesPolten A, Fluharty AL, Fluharty CB, Kappler J, von Figura K, Gieselmann V.N Engl J Med. 1991 Jan 3;324(1):18-22. Lukatela G, Krauss N, Theis K, Selmer T, Gieselmann V, von Figura K, Saenger W. Biochemistry. 1998 Mar 17;37(11):3654-64. same structure, but cant form octamer 1E33 P->L arylsulfatase A -1AUKSunday, July 15, 12 5. Symmetry inQuaternary Structure Cn: cyclic groups, n = 1, Dn: dihedral groups, n = 2, Helical, n = 2XQT: C15 1A6D: D4 1CGM:AU pentamer AU: heterodimerAU monomerBA 15-mer BA 8-mer~80% of all B.A. have symmetryT: tetrahedral, n = 12 O: octahedral, n = 24 I: icosahedral, n = 60 1J2Y: T 1EAB: O1A34: I AU monomerAU monomer AU monomer BA 12-mer BA 24-merBA 60-merSunday, July 15, 12 6. Its (pseudo-) symmetry all over the place Biol AssemblyIntra Chain RNA peptidyltransferase centerRezacova et al Proteins 2007Belousoff et al Biochem Soc.Transact. 20102OGG - trehalose repressor (TreR) effector binding domainSunday, July 15, 12 7. Sunday, July 15, 12 8. How does this relate to protein function?Sunday, July 15, 12 9. CE-Symm new variation of CE that candetect intra-chain pseudyo-symmetries and structuralrepeats PDB ID 3DDV- Transcriptional regulator (GntR family)try it out: http://source.rcsb.orgSunday, July 15, 12 10. N How does CE-Symm workN Variation of standard structure alignment algorithm Allows detection of Circular Permutations by duplication and truncation of atoms N Mask main diagonal of distance matrixSunday, July 15, 12 11. Census of internalpseudo-symmetry ~ 20% of all protein domains have intra-chain pseudo-symmetrySunday, July 15, 12 12. Symmetry around active sites 3HDP - Glyoxalase IFunction along symmetry1KPK - Chloride channelinterfacesSunday, July 15, 12 13. Duplication of active sites as a1XKR - Chemotaxis protein results of internal duplicationsCheC Multiple levels of symmetry 2AAY -EPSP synthetaseSunday, July 15, 12 14. What can we do if we know about internalpseudo-symmetry? Take it for a database search Look at the functionSunday, July 15, 12 15. Example: 3HDP - Glyoxalase-ISunday, July 15, 12 16. Glyoxalase I Many metal binding proteinshave this motifPDB ID 1F9Z- BOUND GLYOXALASE I FROM ESCHERICHIA COLIMolly Min He et. all 2000Sunday, July 15, 12 17. A distant Glyoxalase I relative... GTP binding regulatorjFATCAT structure alignment of 1VR8.A and 3HDP.Aalignment requires 1 twist. There is a central topology-swapped strand.Sunday, July 15, 12 18. Protein with novel fold. Can use symmetry2F9H - PTSIIA/GutA-like to infer conserved sequence motif21% ID in CE-symm alignmentSunday, July 15, 12 19. 2F9H - PTSIIA/GutA-like 21% ID instructure alignmentSunday, July 15, 12 20. green ... blue ... symmetric motifWould be nice to take it into the lab and look atthe function a bit more...Sunday, July 15, 12 21. Hypothesis Hypothesis: pseudo-symmetries are oftenrelated to function Knowledge of pseudo-symmetry also givesclues about evolutionary processesSunday, July 15, 12 22. Implications for Classication Our current approaches for proteinstructure classication cant describeremote relationships on sub-domain levelSunday, July 15, 12 23. Conclusion 80% of all proteins that can form Bio.Assemblies have symmetry 20% of all domains have intra-chain pseudosymmetry Can be linked to function => Valuable to look at intra-chainsymmetries for new proteinstry out CE-Sym : http://source.rcsb.orgSunday, July 15, 12 24. Acknowledgments Spencer E Bliven, Peter Rose, Philippe Youkharibache, Douglas Myers-Turnbull, Phil E BourneSunday, July 15, 12 25. Bonus slideMany propellers have high sequence similarity in their bladesSunday, July 15, 12