Structural and mechanistic insights into the association of PKC alpha -C2 domain to PtdIns(4,5)P sub(2)
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...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 16; pp. 6603 - 6607 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
21.04.2009
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Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 content type line 23 ObjectType-Feature-2 |
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.0813099106 |