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

作者：Samuel R. Chamberlain, Andrea Gohlke, Arooj Shafiq, Iolo Squires, Darerca Owen, Helen R. Mott · 发表于：Proceedings of the National Academy of Sciences · 年份：2021 · DOI：10.1073/pnas.2104219118 · 被引用次数：8 · 研究领域：Protein Kinase Regulation and GTPase Signaling、Cell death mechanisms and regulation、Cellular transport and secretion

-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.