Structural analysis of autoinhibition in the Ras-specific exchange factor RasGRP1
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...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Online |
| Language: | English |
| Published: |
eLife Sciences Publications, Ltd
2013
|
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3728621/ |
| id |
pubmed-3728621 |
|---|---|
| recordtype |
oai_dc |
| spelling |
pubmed-37286212013-08-01 Structural analysis of autoinhibition in the Ras-specific exchange factor RasGRP1 Iwig, Jeffrey S Vercoulen, Yvonne Das, Rahul Barros, Tiago Limnander, Andre Che, Yan Pelton, Jeffrey G Wemmer, David E Roose, Jeroen P Kuriyan, John Biophysics and Structural Biology 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. eLife Sciences Publications, Ltd 2013-07-30 /pmc/articles/PMC3728621/ /pubmed/23908768 http://dx.doi.org/10.7554/eLife.00813 Text en Copyright © 2013, Iwig et al http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Iwig, Jeffrey S Vercoulen, Yvonne Das, Rahul Barros, Tiago Limnander, Andre Che, Yan Pelton, Jeffrey G Wemmer, David E Roose, Jeroen P Kuriyan, John |
| spellingShingle |
Iwig, Jeffrey S Vercoulen, Yvonne Das, Rahul Barros, Tiago Limnander, Andre Che, Yan Pelton, Jeffrey G Wemmer, David E Roose, Jeroen P Kuriyan, John Structural analysis of autoinhibition in the Ras-specific exchange factor RasGRP1 |
| author_facet |
Iwig, Jeffrey S Vercoulen, Yvonne Das, Rahul Barros, Tiago Limnander, Andre Che, Yan Pelton, Jeffrey G Wemmer, David E Roose, Jeroen P Kuriyan, John |
| author_sort |
Iwig, Jeffrey S |
| title |
Structural analysis of autoinhibition in the Ras-specific exchange factor RasGRP1 |
| title_short |
Structural analysis of autoinhibition in the Ras-specific exchange factor RasGRP1 |
| title_full |
Structural analysis of autoinhibition in the Ras-specific exchange factor RasGRP1 |
| title_fullStr |
Structural analysis of autoinhibition in the Ras-specific exchange factor RasGRP1 |
| title_full_unstemmed |
Structural analysis of autoinhibition in the Ras-specific exchange factor RasGRP1 |
| title_sort |
structural analysis of autoinhibition in the ras-specific exchange factor rasgrp1 |
| description |
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. |
| publisher |
eLife Sciences Publications, Ltd |
| publishDate |
2013 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3728621/ |
| _version_ |
1611999381472411648 |