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PMID: 19346474 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Structural and mechanistic insights into the association of PKCalpha-C2 domain to PtdIns(4,5)P2.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 106 ·No. 16 ·2009-04-21 ·Pages 6603-7

Guerrero-Valero M, Ferrer-Orta C, Querol-Audí J, Marin-Vicente C, Fita I, Gómez-Fernández JC, Verdaguer N, Corbalán-García S

Abstract

C2 domains are widely-spread protein signaling motifs that in classical PKCs act as Ca(2+)-binding modules. However, the molecular mechanisms of their targeting process at the plasma membrane remain poorly understood. Here, the crystal structure of PKCalpha-C2 domain in complex with Ca(2+), 1,2-dihexanoyl-sn-glycero-3-[phospho-L-serine] (PtdSer), and 1,2-diayl-sn-glycero-3-[phosphoinositol-4,5-bisphosphate] [PtdIns(4,5)P(2)] shows that PtdSer binds specifically to the calcium-binding region, whereas PtdIns(4,5)P(2) occupies the concave surface of strands beta3 and beta4. Strikingly, the structure reveals a PtdIns(4,5)P(2)-C2 domain-binding mode in which the aromatic residues Tyr-195 and Trp-245 establish direct interactions with the phosphate moieties of the inositol ring. Mutations that abrogate Tyr-195 and Trp-245 recognition of PtdIns(4,5)P(2) severely impaired the ability of PKCalpha to localize to the plasma membrane. Notably, these residues are highly conserved among C2 domains of topology I, and a general mechanism of C2 domain-membrane docking mediated by PtdIns(4,5)P(2) is presented.

MeSH Terms
Amino Acids/metabolism Animals Cations/metabolism Cell Membrane/enzymology Conserved Sequence Genes, Dominant Models, Molecular Mutant Proteins/metabolism PC12 Cells Phosphatidylinositol 4,5-Diphosphate/metabolism Protein Kinase C-alpha/chemistry,metabolism Protein Structure, Secondary Protein Structure, Tertiary Protein Transport Rats Structure-Activity Relationship
Chemicals
Amino Acids Cations Mutant Proteins Phosphatidylinositol 4,5-Diphosphate Protein Kinase C-alpha
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Guerrero-Valero Marta
Department of Bioquímica y Biología Molecular A, Facultad de Veterinaria, Universidad de Murcia, 30100 Murcia, Spain.
Ferrer-Orta Cristina
Querol-Audí Jordi
Marin-Vicente Consuelo
Fita Ignacio
Gómez-Fernández Juan C
Verdaguer Nuria
Corbalán-García Senena
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.0813099106
Published
2009-04-21
Epub
2009-00-03
Pages
6603-7
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2672498
Subset
IM
Databases
PDB
3GPE
External Links
PubMed source DOI: 10.1073/pnas.0813099106 PMC Full Text View journal details
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