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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 16; pp. 6603 - 6607
• Main Authors: Marta Guerrero-Valero, Cristina Ferrer-Orta, Jordi Querol-Audí, Consuelo Marin-Vicente, Ignacio Fita, Juan C. Gómez-Fernández, Nuria Verdaguer, Senena Corbalán-García
• Format: Journal Article
• Language: English
• Published: National Acad Sciences 21.04.2009; National Academy of Sciences
• Subjects: Biological Sciences
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0813099106

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 PKCα-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 β3 and β4. 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 PKCα 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.