On Symmetry and Pseudo-symmetry in proteins Ismb lbr06 prlic
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Transcript of 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 Bourne
Sunday, July 15, 12
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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