The SH3 Domain Acts as a Scaffold for the N-Terminal Intrinsically Disordered Regions of c-Src.
Regulation of c-Src activity by the intrinsically disordered Unique domain has recently been demonstrated. However, its connection with the classical regulatory mechanisms is still missing. Here we show that the Unique domain is part of a long loop closed by the interaction of the SH4 and SH3 domains. The conformational freedom of the Unique domain is further restricted through direct contacts with SH3 that are allosterically modulated by binding of a poly-proline ligand in the presence and in the absence of lipids. Our results highlight the scaffolding role of the SH3 domain for the c-Src N-terminal intrinsically disordered regions and suggest a connection between the regulatory mechanisms involving the SH3 and Unique domains.
BioNMR Laboratory, Organic Chemistry Department, University of Barcelona, Baldiri Reixac 10-12, 08028 Barcelona, Spain.
Mariano
M
Maffei
BioNMR Laboratory, Organic Chemistry Department, University of Barcelona, Baldiri Reixac 10-12, 08028 Barcelona, Spain.
Miguel
M
Arbesú
BioNMR Laboratory, Organic Chemistry Department, University of Barcelona, Baldiri Reixac 10-12, 08028 Barcelona, Spain; Institute for Research in Biomedicine (IRB Barcelona), Baldiri Reixac, 10-12, 08028 Barcelona, Spain.
Anabel-Lise
AL
Le Roux
BioNMR Laboratory, Organic Chemistry Department, University of Barcelona, Baldiri Reixac 10-12, 08028 Barcelona, Spain.
Irene
I
Amata
CNRS UMR5237, University of Montpellier, CRBM, 1919 route de Mende, 34000 Montpellier, France.
Serge
S
Roche
BioNMR Laboratory, Organic Chemistry Department, University of Barcelona, Baldiri Reixac 10-12, 08028 Barcelona, Spain. Electronic address: mpons@ub.edu.
Miquel
M
Pons
D001665:Binding Sites; D000081247:CSK Tyrosine-Protein Kinase; D005786:Gene Expression Regulation; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D008958:Models, Molecular; D011485:Protein Binding; D017433:Protein Structure, Secondary; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018909:src Homology Domains; D019061:src-Family Kinases / Q000737:chemistry* / Q000378:metabolism*
D008055:Lipids; D000081247:CSK Tyrosine-Protein Kinase; D016392:Proto-Oncogene Proteins pp60(c-src); D019061:src-Family Kinases; C000631346:CSK protein, human