Structural analysis of autoinhibition in the Ras-specific exchange factor RasGRP1
Year: 2013
Type: article
Abstract: RasGRP1 and SOS are Ras-specific nucleotide exchange factors that have distinct roles in lymphocyte development. RasGRP1 is important in some cancers and autoimmune diseases but, in contrast to SOS, its regulatory mechanisms are poorly understood. Activating signals lead to the membrane recruitment of RasGRP1 and Ras engagement, but it is unclear how interactions between RasGRP1 and Ras are suppressed in the absence of such signals. We present a crystal structure of a fragment of RasGRP1 in which the Ras-binding site is blocked by an interdomain linker and the membrane-interaction surface of RasGRP1 is hidden within a dimerization interface that may be stabilized by the C-terminal oligomerization domain. NMR data demonstrate that calcium binding to the regulatory module generates substantial conformational changes that are incompatible with the inactive assembly. These features allow RasGRP1 to be maintained in an inactive state that is poised for activation by calcium and membrane-localization signals. DOI:http://dx.doi.org/10.7554/eLife.00813.001.
Source: eLife
DOI: 10.7554/elife.00813
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
Funders: Howard Hughes Medical Institute, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Lawrence Berkeley National Laboratory
Awards: G1695104918, The MIT Center for Single-Cell Dynamics in Cancer (SCDC), G3609659413, Modulation of B cell tolerance checkpoints by distinct Ras/Erk Pathways, Differential regulation of Ras nucleotide exchange factors, Mechanistic Studies of Ras-MAPK Signals: Specialzed Cues for the T cell Lineage?, G7823215421, G9000028586
OpenAlex ID: W2073209241