"LLMs for Python Engineers: Advanced Data Analysis and Semantic Kernel",Oleks...
On Symmetry and Pseudo-symmetry in proteins Ismb lbr06 prlic
1. Internal pseudo-
symmetry in proteins
Andreas Prlić, Spencer E Bliven, Peter Rose, Philippe
Youkharibache, Douglas Myers-Turnbull, Phil E Bourne
Sunday, July 15, 12
3. 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. 2007
Sunday, 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 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 -1AUK
Sunday, July 15, 12
5. 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-‐mer
Sunday, July 15, 12
6. 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 domain
Sunday, July 15, 12
8. • How does this relate to protein function?
Sunday, July 15, 12
9. 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.org
Sunday, July 15, 12
10. 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
matrix
Sunday, July 15, 12
11. Census of internal
pseudo-symmetry
• ~ 20% of all protein domains have intra-
chain pseudo-symmetry
Sunday, July 15, 12
12. •Symmetry around active sites 3HDP - Glyoxalase I
•Function along symmetry 1KPK - Chloride channel
interfaces
Sunday, July 15, 12
13. •Duplication of active sites as a 1XKR - Chemotaxis protein
results of internal duplications CheC
•Multiple levels of symmetry
2AAY -EPSP synthetase
Sunday, July 15, 12
14. • What can we do if we know about internal
pseudo-symmetry?
• Take it for a database search
• Look at the function
Sunday, July 15, 12
16. Glyoxalase I
• Many metal binding proteins
have this motif
PDB ID 1F9Z- BOUND GLYOXALASE I FROM
ESCHERICHIA COLI
Molly Min He et. all 2000
Sunday, July 15, 12
17. 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
18. •Protein with novel fold.
•Can use symmetry 2F9H - PTSIIA/GutA-like
to infer conserved
•sequence motif
21% ID in CE-symm alignment
Sunday, July 15, 12
20. 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
21. Hypothesis
• Hypothesis: pseudo-symmetries are often
related to function
• Knowledge of pseudo-symmetry also gives
clues about evolutionary processes
Sunday, July 15, 12
22. Implications for
Classification
• Our current approaches for protein
structure classification can’t describe
remote relationships on sub-domain level
Sunday, July 15, 12
23. 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
Sunday, July 15, 12
24. Acknowledgments
• Spencer E Bliven,
• Peter Rose,
• Philippe Youkharibache,
• Douglas Myers-Turnbull,
• Phil E Bourne
Sunday, July 15, 12