Dynamic coupling between the SH2 and SH3 domains of c-Src and Hck underlies their inactivation by C-terminal tyrosine phosphorylation.
The effect of C-terminal tyrosine phosphorylation on molecular motions in the Src kinases Hck and c-Src is investigated by molecular dynamics simulations. The SH2 and SH3 domains of the inactive kinases are seen to be tightly coupled by the connector between them, impeding activation. Dephosphorylation of the tail reduces the coupling between the SH2 and SH3 domains in the simulations, as does replacement of connector residues with glycine. A mutational analysis of c-Src expressed in Schizosaccharomyces pombe demonstrates that replacement of residues in the SH2-SH3 connector with glycine activates c-Src. The SH2-SH3 connector appears to be an inducible "snap lock" that clamps the SH2 and SH3 domains upon tail phosphorylation, but which allows flexibility when the tail is released.
Young
M A
MA
Laboratories of Molecular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Gonfloni
S
S
Superti-Furga
G
G
Roux
B
B
Kuriyan
J
J
D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D001681:Biological Assay; D000081247:CSK Tyrosine-Protein Kinase; D002645:Chickens; D003198:Computer Simulation; D004789:Enzyme Activation / Q000235:genetics / Q000502:physiology; D004795:Enzyme Stability / Q000502:physiology; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D011487:Protein Conformation; D011505:Protein-Tyrosine Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000378:metabolism; D051572:Proto-Oncogene Proteins c-hck; D012568:Schizosaccharomyces / Q000187:drug effects / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains / Q000502:physiology*; D019061:src-Family Kinases
D011518:Proto-Oncogene Proteins; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D051572:Proto-Oncogene Proteins c-hck; D019061:src-Family Kinases