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首页> 外文期刊>Nature >Molecular recognition of a single sphingolipid species by a protein's transmembrane domain
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Molecular recognition of a single sphingolipid species by a protein's transmembrane domain

机译：蛋白质跨膜结构域对单个鞘脂种类的分子识别

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摘要

Functioning and processing of membrane proteins critically depend on the way their transmembrane segments are embedded in the membrane1. Sphingolipids are structural components of membranes and can also act as intracellular second messengers. Not much is known of sphingolipids binding to transmembrane domains (TMDs) of proteins within the hydrophobic bilayer, and how this could affect protein function. Here we show a direct and highly specific interaction of exclusively one sphingomyelin species, SM 18, with the TMD of the COPI machinery protein p24 (ref. 2). Strikingly, the interaction depends on both the head-group and the backbone of the sphingolipid, and on a signature sequence (VXXTLXXIY) within the TMD. Molecular dynamics simulations show a close interaction of SM 18 with the TMD. We suggest a role of SM 18 in regulating the equilibrium between an inactive monomeric and an active oligomeric state of the p24 protein3'4, which in turn regulates COPI-dependent transport. Bioinformatic analyses predict that the signature sequence represents a conserved sphingolipid-binding cavity in a variety of mammalian membrane proteins. Thus, in addition to a function as second messengers, sphingolipids can act as cofactors to regulate the function of transmembrane proteins. Our discovery of an unprecedented specificity of interaction of a TMD with an individual sphingolipid species adds to our understanding of why biological membranes are assembled from such a large variety of different lipids.
机译：膜蛋白的功能和加工关键取决于其跨膜片段在膜中的嵌入方式1。鞘脂是膜的结构成分，也可以充当细胞内第二信使。鞘脂与疏水性双层内蛋白质的跨膜结构域（TMDs）结合的了解甚少，而这如何影响蛋白质功能则知之甚少。在这里，我们显示了仅一种鞘磷脂物种SM 18与COPI机械蛋白p24的TMD的直接且高度特异性的相互作用（参考文献2）。令人惊讶的是，相互作用既取决于鞘脂的头基和骨架，也取决于TMD内的签名序列（VXXTLXXIY）。分子动力学模拟表明SM 18与TMD密切相互作用。我们建议SM 18在调节p24蛋白3'4的非活性单体状态和活性寡聚状态之间的平衡中的作用，进而调节COPI依赖性转运。生物信息学分析预测，签名序列代表了多种哺乳动物膜蛋白中保守的鞘脂结合腔。因此，除了作为第二信使的功能外，鞘脂还可以作为辅助因子来调节跨膜蛋白的功能。我们对TMD与单个鞘脂类物种相互作用的前所未有的特异性的发现，加深了我们对为何从如此众多的不同脂质组装生物膜的理解。

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  • 来源
    《Nature》 |2012年第7382期|p.525-529|共5页
  • 作者

    F.-Xabier Contreras; Andreas M. Ernst; Per Haberkant; Patrik Bjoerkholm; Erik Lindahl; Basak Goenen; Christian Tischer; Arne Elofsson; Gunnar von Heijne; ChristophThiele; Rainer Pepperkok; Felix Wieland; Britta Bruegger;

  • 作者单位

    Heidelberg University Biochemistry Center, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.;

    Heidelberg University Biochemistry Center, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.;

    Heidelberg University Biochemistry Center, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.;

    Center for Biomembrane Research, Department of Biochemistry and Biophysics, Stockholm University, SE-106 91 Stockholm, Sweden.,Stockholm Bioinformatics Center, Science for Life Laboratory Stockholm University, Box 1031, SE-171 21 Solna, Sweden.;

    Center for Biomembrane Research, Department of Biochemistry and Biophysics, Stockholm University, SE-106 91 Stockholm, Sweden.,Theoretical & Computational Biophysics, Royal Institute of Technology, AlbaNova University Centre, SE-106 91 Stockholm, Sweden.;

    Heidelberg University Biochemistry Center, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.;

    ALMF, EMBL, Meyerhofstrasse 1,69117 Heidelberg, Germany.;

    Center for Biomembrane Research, Department of Biochemistry and Biophysics, Stockholm University, SE-106 91 Stockholm, Sweden.,Stockholm Bioinformatics Center, Science for Life Laboratory Stockholm University, Box 1031, SE-171 21 Solna, Sweden.;

    Center for Biomembrane Research, Department of Biochemistry and Biophysics, Stockholm University, SE-106 91 Stockholm, Sweden.,Stockholm Bioinformatics Center, Science for Life Laboratory Stockholm University, Box 1031, SE-171 21 Solna, Sweden.;

    UMES Life and Medical Sciences Institute, Carl-Troll-Strasse 31, 53115 Bonn, Germany;

    ALMF, EMBL, Meyerhofstrasse 1,69117 Heidelberg, Germany.;

    Heidelberg University Biochemistry Center, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.;

    Heidelberg University Biochemistry Center, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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