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Type: Journal article
Title: Structural basis for phosphatidylinositol phosphate kinaseType Iγ binding to talin at focal adhesions
Other Titles: Structural basis for phosphatidylinositol phosphate kinase type Igamma binding to talin at focal adhesions
Author: de Pereda, J.
Wegener, K.
Santelli, E.
Bate, N.
Ginsberg, M.
Critchley, D.
Campbell, I.
Liddington, R.
Citation: Journal of Biological Chemistry, 2005; 280(9):8381-8386
Publisher: Amer Soc Biochemistry Molecular Biology Inc
Issue Date: 2005
ISSN: 0021-9258
Statement of
Jose M. de Pereda, Kate L. Wegener, Eugenio Santelli, Neil Bate, Mark H. Ginsberg, David R. Critchley, Iain D. Campbell and Robert C. Liddington
Abstract: The 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.
Keywords: Focal Adhesions
Phosphotransferases (Alcohol Group Acceptor)
Integrin beta Chains
DNA, Complementary
Crystallography, X-Ray
Magnetic Resonance Spectroscopy
Gene Deletion
Binding Sites
Amino Acid Motifs
Protein Conformation
Protein Structure, Tertiary
Protein Binding
Models, Molecular
Rights: © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.
DOI: 10.1074/jbc.M413180200
Appears in Collections:Aurora harvest
Molecular and Biomedical Science publications

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