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Calmodulin extracts the Ras family protein RalA from lipid bilayers by engagement with two membrane-targeting motifs.

Accepted version
Peer-reviewed

Type

Article

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Abstract

RalA is a small GTPase and a member of the Ras family. This molecular switch is activated downstream of Ras and is widely implicated in tumor formation and growth. Previous work has shown that the ubiquitous Ca2+-sensor calmodulin (CaM) binds to small GTPases such as RalA and K-Ras4B, but a lack of structural information has obscured the functional consequences of these interactions. Here, we have investigated the binding of CaM to RalA and found that CaM interacts exclusively with the C terminus of RalA, which is lipidated with a prenyl group in vivo to aid membrane attachment. Biophysical and structural analyses show that the two RalA membrane-targeting motifs (the prenyl anchor and the polybasic motif) are engaged by distinct lobes of CaM and that CaM binding leads to removal of RalA from its membrane environment. The structure of this complex, along with a biophysical investigation into membrane removal, provides a framework with which to understand how CaM regulates the function of RalA and sheds light on the interaction of CaM with other small GTPases, including K-Ras4B.

Description

Keywords

K-Ras, Ral, calmodulin, membrane, nuclear magnetic resonance, Amino Acid Motifs, Binding Sites, Calmodulin, Cell Membrane, Humans, Lipid Bilayers, Molecular Structure, Nuclear Magnetic Resonance, Biomolecular, Phosphorylation, Protein Binding, Protein Prenylation, Serine, ral GTP-Binding Proteins

Journal Title

Proc Natl Acad Sci U S A

Conference Name

Journal ISSN

0027-8424
1091-6490

Volume Title

118

Publisher

Proceedings of the National Academy of Sciences

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All rights reserved
Sponsorship
Biotechnology and Biological Sciences Research Council (BB/E013228/1)
BBSRC (BB/P504835/1)
Biotechnology and Biological Sciences Research Council (1790106)