title: Lipid-Sorting Specificity Encoded in K-Ras Membrane Anchor Regulates Signal Output.
abstract: K-Ras is targeted to the plasma membrane by a C-terminal membrane anchor that comprises a farnesyl-cysteine-methyl-ester and a polybasic domain. We used quantitative spatial imaging and atomistic molecular dynamics simulations to examine molecular details of K-Ras plasma membrane binding. We found that the K-Ras anchor binds selected plasma membrane anionic lipids with defined head groups and lipid side chains. The precise amino acid sequence and prenyl group define a combinatorial code for lipid binding that extends beyond simple electrostatics; within this code lysine and arginine residues are non-equivalent and prenyl chain length modifies nascent polybasic domain lipid preferences. The code is realized by distinct dynamic tertiary structures of the anchor on the plasma membrane that govern amino acid side-chain-lipid interactions. An important consequence of this specificity is the ability of such anchors when aggregated to sort subsets of phospholipids into nanoclusters with defined lipid compositions that determine K-Ras signaling output.
authors.affiliation: Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX 77030, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX 77030, USA.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Prakash
authors.affiliation: Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX 77030, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Liang
authors.affiliation: Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX 77030, USA.
authors.forename: Kwang-Jin
authors.initials: KJ
authors.lastname: Cho
authors.affiliation: Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX 77030, USA. Electronic address: alemayehu.g.abebe@uth.tmc.edu.
authors.forename: Alemayehu A
authors.initials: AA
authors.lastname: Gorfe
authors.affiliation: Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX 77030, USA. Electronic address: john.f.hancock@uth.tmc.edu.
authors.forename: John F
authors.initials: JF
authors.lastname: Hancock
mesh_terms: D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009154:Mutation; D009387:Neoprene / Q000737:chemistry / Q000378:metabolism; D000072417:Protein Domains; D016283:Proto-Oncogene Proteins p21(ras) / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: C117307:KRAS protein, human; D008055:Lipids; C016077:prenyl; D009387:Neoprene; D016283:Proto-Oncogene Proteins p21(ras)
keywords: K-RAS; electron microscopy; molecular dynamics; nanoclustering; phosphatidylserine; polybasic domain