Structural Analysis of Autoinhibition in the Ras-specific Exchange Factor RasGRP1

Overview

Journal Elife

Specialty Biology

Date 2013 Aug 3

PMID 23908768

Citations 51

Authors

Jeffrey S Iwig

Yvonne Vercoulen

Rahul Das

Tiago Barros

Andre Limnander

Yan Che

Jeffrey G Pelton

David E Wemmer

Jeroen P Roose

John Kuriyan

Affiliations

Soon will be listed here.

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.

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