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Title

Structural Basis for Phosphatidylinositol Phosphate Kinase Type Iγ Binding to Talin at Focal Adhesions

AuthorsPereda, José M. de
Issue Date2005
PublisherAmerican Society for Biochemistry and Molecular Biology
CitationJournal of Biological Chemistry 280(9): 8381-8386 (2005)
AbstractThe cytoskeletal protein talin binds to a short C-terminal sequence in phosphatidylinositol phosphate kinase type Iγ (PIPKIγ), activating the enzyme and promoting the local production of phosphatidylinositol 4,5 bisphosphate, which regulates focal adhesion dynamics as well as clathrin-mediated endocytosis in neuronal cells. Here we show by crystallographic, NMR, and calorimetric analysis that the phosphotyrosine binding (PTB)-like domain of talin engages the PIPKIγ C terminus in a mode very similar to that of integrin binding. However, PIPKIγ binds in the canonical PTB-peptide mode with an SPLH motif replacing the classic NPXY motif. The tighter packing of the SPLH motif against the hydrophobic core of talin may explain the stronger binding of PIPKIγ. Two tyrosine residues flanking the SPLH motif (Tyr-644 and Tyr-649) have been implicated in the regulation of talin binding. We show that phosphorylation at Tyr-644, a Src phosphorylation site in vivo, has little effect on the binding mode or strength, which is consistent with modeling studies in which the phosphotyrosine makes surface-exposed salt bridges, and we suggest that its strong activating effect arises from the release of autoinhibitory restraints in the full-length PIPKIγ. Modeling studies suggest that phosphorylation of Tyr-649 will likewise have little effect on talin binding, whereas phosphorylation of the SPLH serine is predicted to be strongly disruptive. Our data are consistent with the proposal that Src activity promotes a switch from integrin binding to PIPKIγ binding that regulates focal adhesion turnover. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.
URIhttp://hdl.handle.net/10261/63062
DOI10.1074/jbc.M413180200
Identifiersdoi: 10.1074/jbc.M413180200
issn: 0021-9258
e-issn: 1083-351X
Appears in Collections:(IBMCC) Artículos
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