Structural and functional studies of the Ras-associating and pleckstrin-homology domains of Grb10 and Grb14
Open Access
- 2 August 2009
- journal article
- research article
- Published by Springer Nature in Nature Structural & Molecular Biology
- Vol. 16 (8), 833-839
- https://doi.org/10.1038/nsmb.1642
Abstract
Grb10 and Grb14 are adaptor proteins that inhibit insulin signaling through direct interactions with the insulin receptor kinase domain. Structural and functional studies now reveal that the tandem Ras-associating and pleckstrin-homology domains of these proteins are necessary for membrane recruitment and insulin receptor inhibition. 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-Å 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.Keywords
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