title: Lipid binding by the Unique and SH3 domains of c-Src suggests a new regulatory mechanism.
abstract: c-Src is a non-receptor tyrosine kinase involved in numerous signal transduction pathways. The kinase, SH3 and SH2 domains of c-Src are attached to the membrane-anchoring SH4 domain through the flexible Unique domain. Here we show intra- and intermolecular interactions involving the Unique and SH3 domains suggesting the presence of a previously unrecognized additional regulation layer in c-Src. We have characterized lipid binding by the Unique and SH3 domains, their intramolecular interaction and its allosteric modulation by a SH3-binding peptide or by Calcium-loaded calmodulin binding to the Unique domain. We also show reduced lipid binding following phosphorylation at conserved sites of the Unique domain. Finally, we show that injection of full-length c-Src with mutations that abolish lipid binding by the Unique domain causes a strong in vivo phenotype distinct from that of wild-type c-Src in a Xenopus oocyte model system, confirming the functional role of the Unique domain in c-Src regulation.
authors: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
authors: Yolanda
authors: Y
authors: Pérez
authors: Mariano
authors: M
authors: Maffei
authors: Ana
authors: A
authors: Igea
authors: Irene
authors: I
authors: Amata
authors: Margarida
authors: M
authors: Gairí
authors: Angel R
authors: AR
authors: Nebreda
authors: Pau
authors: P
authors: Bernadó
authors: Miquel
authors: M
authors: Pons
mesh_terms: D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002147:Calmodulin / Q000737:chemistry / Q000378:metabolism; D002645:Chickens; D004134:Dimyristoylphosphatidylcholine / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D010715:Phosphatidylglycerols / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D014981:Xenopus / Q000254:growth & development; D018909:src Homology Domains; D019061:src-Family Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D002147:Calmodulin; D008055:Lipids; D010455:Peptides; D010715:Phosphatidylglycerols; C011083:polyproline; C002773:dimyristoylphosphatidylglycerol; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D004134:Dimyristoylphosphatidylcholine