Structural and mechanistic insights into the association of PKC alpha -C2 domain to PtdIns(4,5)P sub(2)

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 16; pp. 6603 - 6607
• Main Authors: Guerrero-Valero, Marta, Ferrer-Orta, Cristina, Querol-Aud­, Jordi, Marin-Vicente, Consuelo, Fita, Ignacio, Gomez-Fernandez, Juan C, Verdaguer, Nuria, Corbalan-Garc­a, Senena
• Format: Journal Article
• Language: English
• Published: 21.04.2009
• 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 super(2+)-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 Ca super(2+), 1,2-dihexanoyl-sn-glycero-3- [phospho-l-serine] (PtdSer), and 1,2-diayl-sn-glycero-3-[phosphoinositol-4,5-bisphosphate] [PtdIns P sub(2)] shows that PtdSer binds specifically to the calcium-binding region, whereas PtdIns P sub(2) occupies the concave surface of strands beta 3 and beta 4. Strikingly, the structure reveals a PtdIns P sub(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 P sub(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 P sub(2) is presented.