Structural and Functional Studies of the Ras-Associating and Pleckstrin Homology Domains of Grb10 and Grb14

Journal Article · Thu Jan 01 04:00:00 EST 2009 · Nature Structural and Molecular Biology

DOI:https://doi.org/10.1038/nsmb1209-1331a· OSTI ID:980494

Depetris, R; Wu, J; Hubbard, S

Growth factor receptor-binding proteins Grb7, Grb10 and Grb14 are adaptor proteins containing a Ras-associating (RA) domain, a pleckstrin-homology (PH) domain, a family-specific BPS (between PH and SH2) region and a C-terminal Src-homology-2 domain. Previous structural studies showed that the Grb14 BPS region binds as a pseudosubstrate inhibitor in the tyrosine kinase domain of the insulin receptor to suppress insulin signaling. Here we report the crystal structure of the RA and PH domains of Grb10 at 2.6-A resolution. The structure reveals that these two domains, along with the intervening linker, form an integrated, dimeric structural unit. Biochemical studies demonstrated that Grb14 binds to activated Ras, which may serve as a timing mechanism for downregulation of insulin signaling. Our results illuminate the membrane-recruitment mechanisms not only of Grb7, Grb10 and Grb14 but also of MIG-10, Rap1-interacting adaptor molecule, lamellipodin and Pico, proteins involved in actin-cytoskeleton rearrangement that share a structurally related RA-PH tandem unit.

• Research Organization: Brookhaven National Laboratory (BNL) National Synchrotron Light Source
• Sponsoring Organization: Doe - Office Of Science
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 980494
• Report Number(s): BNL--93412-2010-JA
• Journal Information: Nature Structural and Molecular Biology, Journal Name: Nature Structural and Molecular Biology Journal Issue: 8 Vol. 16; ISSN 1072-8368
• Country of Publication: United States
• Language: English

Related Subjects

36 MATERIALS SCIENCE
CRYSTAL STRUCTURE
FUNCTIONALS
GROWTH FACTORS
INSULIN
PHOSPHOTRANSFERASES
PROTEINS
RECEPTORS
RESOLUTION
TYROSINE
national synchrotron light source