Internal pseudo-symmetry in proteins

Andreas Prlić, Spencer E Bliven, Peter Rose, Philippe Youkharibache, Douglas Myers-Turnbull, Phil E Bourne

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source: www.rcsb.org

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Biol. Assemblies in PDB

• Bio. Assembly assigned by

• Author

• calculation (PQS, PISA* and curation)

One asymunit

1 Bio. parts of a Bio. multiple Bio.

* E. Krissinel and K. Henrick, J. Mol. Biol. 2007

2hhb 1hho 1h4v

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Biol. Assemb. & DiseaseSNP:rs28940893 causes Metachromatic leukodystrophy (lysosomal storage disorder)

... 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 polypeptidesPolten A, Fluharty AL, Fluharty CB, Kappler J, von Figura K, Gieselmann V.N Engl J Med. 1991 Jan 3;324(1):18-22.

same structure, but can’t form octamer 1E33P->L

Lukatela G, Krauss N, Theis K, Selmer T, Gieselmann V, von Figura K, Saenger W.Biochemistry. 1998 Mar 17;37(11):3654-64.

arylsulfatase A -1AUK

asym unit

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Symmetry in Quaternary Structure

Cn:  cyclic  groups,  n  =  1,  … Dn:  dihedral  groups,  n  =  2,  … Helical,  n  =  ∞

T:  tetrahedral,  n  =  12 O:  octahedral,  n  =  24 I:  icosahedral,  n  =  60

1J2Y:  TAU  monomerBA  12-­‐mer

1EAB:  OAU  monomerBA  24-­‐mer

1A34:  IAU  monomerBA  60-­‐mer

2XQT:  C15AU  pentamerBA  15-­‐mer

1CGM:AU  monomer

1A6D:  D4AU:  heterodimerBA  8-­‐mer

~80% of all B.A. have symmetry

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It’s (pseudo-) symmetry all over the place

RNA

peptidyltransferase center

Biol Assembly Intra Chain

2OGG - trehalose repressor (TreR) effector binding domain

Rezacova et al Proteins 2007Belousoff et al Biochem Soc.

Transact. 2010

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• How does this relate to protein function?

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CE-Symm

• new variation of CE that candetect intra-chain pseudyo- symmetries and structural repeats

PDB ID 3DDV- Transcriptional regulator (GntR family)

try it out: http://source.rcsb.orgSunday, July 15, 12

How does CE-Symm workVariation of standard structure

alignment algorithm

Allows detection of Circular Permutations by duplication and

truncation of atoms

Mask main diagonal of distance matrix

N

N

N

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• ~ 20% of all protein domains have intra-chain pseudo-symmetry

Census of internal pseudo-symmetry

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1KPK - Chloride channel

3HDP - Glyoxalase I•Symmetry around active sites

•Function along symmetry interfaces

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2AAY -EPSP synthetase

•Duplication of active sites as a results of internal duplications

•Multiple levels of symmetry

1XKR - Chemotaxis protein CheC

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• What can we do if we know about internal pseudo-symmetry?

• Take it for a database search

• Look at the function

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Example: 3HDP - Glyoxalase-I

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Glyoxalase I

• Many metal binding proteins have this motif

PDB ID 1F9Z- BOUND GLYOXALASE I FROM ESCHERICHIA COLI

Molly Min He et. all 2000

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A distant Glyoxalase I relative... GTP binding regulator

jFATCAT structure alignment of 1VR8.A and 3HDP.Aalignment requires 1 twist. There is a central topology-swapped strand.

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2F9H - PTSIIA/GutA-like•Protein with novel fold. •Can use symmetryto infer conserved •sequence motif

21% ID in CE-symm alignment

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21% ID in structure alignment

2F9H - PTSIIA/GutA-like

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green ...

blue ... symmetric motif

Would be nice to take it into the lab and look at the function a bit more...

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Hypothesis

• Hypothesis: pseudo-symmetries are often related to function

• Knowledge of pseudo-symmetry also gives clues about evolutionary processes

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Implications for Classification

• Our current approaches for protein structure classification can’t describe remote relationships on sub-domain level

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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.org

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Acknowledgments

• Spencer E Bliven,

• Peter Rose,

• Philippe Youkharibache,

• Douglas Myers-Turnbull,

• Phil E Bourne

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Many propellers have high sequence

similarity in their blades

Bonus slide

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