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  Ras GTPase activating (RasGAP) activity of the dual specificity GAP protein Rasal requires colocalization and C2 domain binding to lipid membranes

Sot, B., Behrmann, E., Raunser, S., & Wittinghofer, A. (2013). Ras GTPase activating (RasGAP) activity of the dual specificity GAP protein Rasal requires colocalization and C2 domain binding to lipid membranes. Proceedings of the National Academy of Sciences of the United States of America, 110(1), 111-6. doi:10.1073/pnas.1201658110.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-63C9-3 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002B-6146-2
Genre: Journal Article

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Sot-2013-Ras GTPase activating (RasGAP) activi.pdf (Any fulltext), 866KB
 
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Sot, B., Author
Behrmann, E.1, Author
Raunser, S., Author
Wittinghofer, A., Author
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1External Organizations, ou_persistent22              

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Free keywords: Allosteric Regulation/physiology Amino Acid Sequence Electrophoresis, Polyacrylamide Gel Enzyme Activation/physiology Escherichia coli Humans Lipid Bilayers/*metabolism Microscopy, Electron Molecular Sequence Data Phosphatidylinositol Phosphates/metabolism Phosphatidylserines/metabolism *Protein Conformation Protein Structure, Tertiary p120 GTPase Activating Protein/genetics/*metabolism
 Abstract: Rasal, belonging to the GAP1 subfamily of Ras GTPase-activating proteins (RasGAPs) with dual RasGAP/RapGAP specificity, is epigenetically silenced in several tumor types. Surprisingly, the isolated protein has GAP activity on Rap but not on Ras. Its membrane recruitment is regulated by interaction with calcium and lipids, which simultaneously induces its RasGAP activity through a yet unknown mechanism. Here we show that the interaction of Rasal with membranes induces Rasal RasGAP activity by spatial and conformational regulation, although it does not have any effect on its RapGAP activity. Not only is colocalization of Rasal and Ras in the membrane essential for RasGAP activation, but direct and Ca-dependent interaction between the tandem C2 domains of Rasal and lipids of the membrane is also required. Whereas the C2A domain binds specifically phosphatidylserine, the C2B domain interacts with several phosphoinositol lipids. Finally we show, that similar to the C2 domains of synaptotagmins, the Rasal tandem C2 domains are able to sense and induce membrane curvature by the insertion of hydrophobic loops into the membrane.

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 Dates: 2013
 Publication Status: Published in print
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 Rev. Type: -
 Identifiers: Other: 23251034
DOI: 10.1073/pnas.1201658110
ISSN: 1091-6490 (Electronic)
ISSN: 0027-8424 (Linking)
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Title: Proceedings of the National Academy of Sciences of the United States of America
  Alternative Title : Proc. Natl. Acad. Sci. USA
Source Genre: Journal
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Pages: - Volume / Issue: 110 (1) Sequence Number: - Start / End Page: 111 - 6 Identifier: -