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...
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Format: | Article |
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eLife Sciences Publications Ltd
2013-07-01
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Series: | eLife |
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Online Access: | https://elifesciences.org/articles/00813 |
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author | Jeffrey S Iwig Yvonne Vercoulen Rahul Das Tiago Barros Andre Limnander Yan Che Jeffrey G Pelton David E Wemmer Jeroen P Roose John Kuriyan |
author_facet | Jeffrey S Iwig Yvonne Vercoulen Rahul Das Tiago Barros Andre Limnander Yan Che Jeffrey G Pelton David E Wemmer Jeroen P Roose John Kuriyan |
author_sort | Jeffrey S Iwig |
collection | DOAJ |
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. |
first_indexed | 2024-04-11T09:05:49Z |
format | Article |
id | doaj.art-22dd1a80e4fd424caaffaa2efb2b12f3 |
institution | Directory Open Access Journal |
issn | 2050-084X |
language | English |
last_indexed | 2024-04-11T09:05:49Z |
publishDate | 2013-07-01 |
publisher | eLife Sciences Publications Ltd |
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series | eLife |
spelling | doaj.art-22dd1a80e4fd424caaffaa2efb2b12f32022-12-22T04:32:37ZengeLife Sciences Publications LtdeLife2050-084X2013-07-01210.7554/eLife.00813Structural analysis of autoinhibition in the Ras-specific exchange factor RasGRP1Jeffrey S Iwig0Yvonne Vercoulen1Rahul Das2Tiago Barros3Andre Limnander4Yan Che5Jeffrey G Pelton6David E Wemmer7Jeroen P Roose8John Kuriyan9Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United StatesDepartment of Anatomy, University of California, San Francisco, San Francisco, United StatesDepartment of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United StatesDepartment of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United StatesDepartment of Anatomy, University of California, San Francisco, San Francisco, United StatesDepartment of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United StatesCalifornia Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United StatesCalifornia Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States; Department of Chemistry, University of California, Berkeley, Berkeley, United States; Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, United StatesDepartment of Anatomy, University of California, San Francisco, San Francisco, United StatesDepartment of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States; Department of Chemistry, University of California, Berkeley, Berkeley, United States; Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, United StatesRasGRP1 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.https://elifesciences.org/articles/00813cell signalingnucleotide exchange factordiacylglycerol |
spellingShingle | Jeffrey S Iwig Yvonne Vercoulen Rahul Das Tiago Barros Andre Limnander Yan Che Jeffrey G Pelton David E Wemmer Jeroen P Roose John Kuriyan Structural analysis of autoinhibition in the Ras-specific exchange factor RasGRP1 eLife cell signaling nucleotide exchange factor diacylglycerol |
title | 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_short | Structural analysis of autoinhibition in the Ras-specific exchange factor RasGRP1 |
title_sort | structural analysis of autoinhibition in the ras specific exchange factor rasgrp1 |
topic | cell signaling nucleotide exchange factor diacylglycerol |
url | https://elifesciences.org/articles/00813 |
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