The Unique Domain Forms a Fuzzy Intramolecular Complex in Src Family Kinases.
The N-terminal regulatory region of c-Src including the SH4, Unique, and SH3 domains adopts a compact, yet highly dynamic, structure that can be described as an intramolecular fuzzy complex. Most of the long-range interactions within the Unique domain are also observed in constructs lacking the structured SH3, indicating a considerable degree of preorganization of the disordered Unique domain. Here we report that members of the Src family of kinases (SFK) share well-conserved sequence features involving aromatic residues in their Unique domains. This observation contrasts with the supposed lack of sequence homology implied by the name of these domains and suggests that the other members of SFK also have a regulatory region involving their Unique domains. We argue that the Unique domain of each SFK is sensitive to specific input signals, encoded by each specific sequence, but the entire family shares a common mechanism for connecting the disordered and structured domains.
BioNMR Laboratory, Inorganic and Organic Chemistry Department, Universitat de Barcelona, Baldiri Reixac 10-12, 08028 Barcelona, Spain.
Miguel
M
Arbesú
BioNMR Laboratory, Inorganic and Organic Chemistry Department, Universitat de Barcelona, Baldiri Reixac 10-12, 08028 Barcelona, Spain.
Mariano
M
Maffei
Centre de Biochimie Structurale, INSERM U1054, CNRS UMR 5048, Université Montpellier 1 and 2, 34092 Montpellier, France; Instituto de Tecnologia Química e Biológica António Xavier, ITQB NOVA, Avenida da República, 2780-157 Oeiras, Portugal.
Tiago N
TN
Cordeiro
BioNMR Laboratory, Inorganic and Organic Chemistry Department, Universitat de Barcelona, Baldiri Reixac 10-12, 08028 Barcelona, Spain.
João M C
JM
Teixeira
BioNMR Laboratory, Inorganic and Organic Chemistry Department, Universitat de Barcelona, Baldiri Reixac 10-12, 08028 Barcelona, Spain.
Yolanda
Y
Pérez
Centre de Biochimie Structurale, INSERM U1054, CNRS UMR 5048, Université Montpellier 1 and 2, 34092 Montpellier, France.
Pau
P
Bernadó
CNRS UMR5237, University of Montpellier, CRBM, 1919 route de Mende, 34000 Montpellier, France.
Serge
S
Roche
BioNMR Laboratory, Inorganic and Organic Chemistry Department, Universitat de Barcelona, Baldiri Reixac 10-12, 08028 Barcelona, Spain. Electronic address: mpons@ub.edu.
Miquel
M
Pons
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001665:Binding Sites; D017124:Conserved Sequence; D017143:Fuzzy Logic; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D019061:src-Family Kinases / Q000737:chemistry*
D019061:src-Family Kinases
SH3; SH4; Src family kinases; c-Src; fuzzy complex; intrinsically disordered proteins; preorganization; protein scaffold; unique domain