Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 16, Pages 6603-6607Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0813099106
Keywords
calcium phosphoinositides; peripheral membrane proteins
Categories
Funding
- Fundacion Medica Mutua Madrilena
- Fundacion Ramon Areces
- Fundacion Seneca [08700/PI/08]
- Ministerio de Ciencia e Innovacion [BFU2005-02482, BFU2008-01010, BFU2005-02376/BMC, BFU2005-08686-C02-01]
- European Synchrotron Radiation Facility
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C2 domains are widely-spread protein signaling motifs that in classical PKCs act as Ca2+-binding modules. However, the molecular mechanisms of their targeting process at the plasma membrane remain poorly understood. Here, the crystal structure of PKC alpha-C2 domain in complex with Ca2+, 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 beta 3 and beta 4. 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 PKC alpha 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.
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