Structural basis for inhibition of the insulin receptor by the adaptor protein Grb14.
Grb14, a member of the Grb7 adaptor protein family, possesses a pleckstrin homology (PH) domain, a C-terminal Src homology-2 (SH2) domain, and an intervening stretch of approximately 45 residues known as the BPS region, which is unique to this adaptor family. Previous studies have demonstrated that Grb14 is a tissue-specific negative regulator of insulin receptor signaling and that inhibition is mediated by the BPS region. We have determined the crystal structure of the Grb14 BPS region in complex with the tyrosine kinase domain of the insulin receptor. The structure reveals that the N-terminal portion of the BPS region binds as a pseudosubstrate inhibitor in the substrate peptide binding groove of the kinase. Together with the crystal structure of the SH2 domain, we present a model for the interaction of Grb14 with the insulin receptor, which indicates how Grb14 functions as a selective protein inhibitor of insulin signaling.
Depetris
Rafael S
RS
Structural Biology Program, Skirball Institute of Biomolecular Medicine and Department of Pharmacology, New York University School of Medicine, New York, New York 10016, USA.
Hu
Junjie
J
Gimpelevich
Ilana
I
Holt
Lowenna J
LJ
Daly
Roger J
RJ
Hubbard
Stevan R
SR
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D018360:Crystallography, X-Ray; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D008958:Models, Molecular; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000494:pharmacology*; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; C099655:GRB14 protein, human; D007328:Insulin; D011506:Proteins; D011972:Receptor, Insulin