On Symmetry and Pseudo-symmetry in proteins Ismb lbr06 prlic

Internal pseudo- symmetry in proteins Andreas Prlić, Spencer E Bliven, Peter Rose, Philippe Youkharibache, Douglas Myers-Turnbull, Phil E BourneSunday, July 15, 12

source: www.rcsb.orgSunday, July 15, 12

Biol. Assemblies in PDB 1 Bio. parts of a Bio. multiple Bio. One asym unit 2hhb 1hho 1h4v • Bio. Assembly assigned by • Author • calculation (PQS, PISA* and curation) * E. Krissinel and K. Henrick, J. Mol. Biol. 2007Sunday, July 15, 12

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 of arylsulfatase A to lysosomal cysteine proteinases and results in a severe reduction in the half-life of the mutant polypeptides Polten 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 can’t form octamer 1E33 P->L arylsulfatase A -1AUKSunday, July 15, 12

Symmetry in Quaternary Structure Cn: cyclic groups, n = 1, … Dn: dihedral groups, n = 2, … Helical, n = ∞ 2XQT: C15 1A6D: D4 1CGM: AU pentamer AU: heterodimer AU monomer BA 15-‐mer BA 8-‐mer ~80% of all B.A. have symmetry T: tetrahedral, n = 12 O: octahedral, n = 24 I: icosahedral, n = 60 1J2Y: T 1EAB: O 1A34: I AU monomer AU monomer AU monomer BA 12-‐mer BA 24-‐mer BA 60-‐merSunday, July 15, 12

It’s (pseudo-) symmetry all over the place Biol Assembly Intra Chain RNA peptidyltransferase center Rezacova et al Proteins 2007 Belousoff et al Biochem Soc. Transact. 2010 2OGG - trehalose repressor (TreR) effector binding domainSunday, July 15, 12

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• How does this relate to protein function?Sunday, July 15, 12

CE-Symm • new variation of CE that can detect intra-chain pseudyo- symmetries and structural repeats PDB ID 3DDV- Transcriptional regulator (GntR family) try it out: http://source.rcsb.orgSunday, July 15, 12

N How does CE-Symm work N 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

Census of internal pseudo-symmetry • ~ 20% of all protein domains have intra- chain pseudo-symmetrySunday, July 15, 12

•Symmetry around active sites 3HDP - Glyoxalase I •Function along symmetry 1KPK - Chloride channel interfacesSunday, July 15, 12

•Duplication of active sites as a 1XKR - Chemotaxis protein results of internal duplications CheC •Multiple levels of symmetry 2AAY -EPSP synthetaseSunday, July 15, 12

• What can we do if we know about internal pseudo-symmetry? • Take it for a database search • Look at the functionSunday, July 15, 12

Example: 3HDP - Glyoxalase-ISunday, July 15, 12

Glyoxalase I • Many metal binding proteins have this motif PDB ID 1F9Z- BOUND GLYOXALASE I FROM ESCHERICHIA COLI Molly Min He et. all 2000Sunday, July 15, 12

A distant Glyoxalase I relative... GTP binding regulator jFATCAT structure alignment of 1VR8.A and 3HDP.A alignment requires 1 twist. There is a central topology-swapped strand.Sunday, July 15, 12

•Protein with novel fold. •Can use symmetry 2F9H - PTSIIA/GutA-like to infer conserved •sequence motif 21% ID in CE-symm alignmentSunday, July 15, 12

2F9H - PTSIIA/GutA-like 21% ID in structure alignmentSunday, July 15, 12

green ... blue ... symmetric motif Would be nice to take it into the lab and look at the function a bit more...Sunday, July 15, 12

Hypothesis • Hypothesis: pseudo-symmetries are often related to function • Knowledge of pseudo-symmetry also gives clues about evolutionary processesSunday, July 15, 12

Implications for Classiﬁcation • Our current approaches for protein structure classiﬁcation can’t describe remote relationships on sub-domain levelSunday, July 15, 12

Conclusion • 80% of all proteins that can form Bio. Assemblies have symmetry • 20% of all domains have intra-chain pseudo symmetry • Can be linked to function • => Valuable to look at intra-chain symmetries for new proteins try out CE-Sym : http://source.rcsb.orgSunday, July 15, 12

Acknowledgments • Spencer E Bliven, • Peter Rose, • Philippe Youkharibache, • Douglas Myers-Turnbull, • Phil E BourneSunday, July 15, 12

Bonus slideMany propellers have high sequence similarity in their bladesSunday, July 15, 12

On Symmetry and Pseudo-symmetry in proteins Ismb lbr06 prlic

by Andreas Prlić on Jul 15, 2012

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