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Structural insights into adiponectin receptors suggest ceramidase activity

机译：对脂联素受体的结构见解提示了神经酰胺酶活性

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摘要

Adiponectin receptors (ADIPORs) are integral membrane proteins that control glucose and lipid metabolism by mediating, at least in part, a cellular ceramidase activity1 that catalyses the hydrolysis of ceramide to produce sphingosine and a free fatty acid (FFA). The crystal structures of the two receptor subtypes, ADIPOR1 and ADIPOR2, show a similar overall seven-transmembrane-domain architecture with large unoccupied cavities and a zinc binding site within the seven transmembrane domain2. However, the molecular mechanisms by which ADIPORs function are not known. Here we describe the crystal structure of ADIPOR2 bound to a FFA molecule and show that ADIPOR2 possesses intrinsic basal ceramidase activity that is enhanced by adiponectin. We also identify a ceramide binding pose and propose a possible mechanism for the hydrolytic activity of ADIPOR2 using computational approaches. In molecular dynamics simulations, the side chains of residues coordinating the zinc rearrange quickly to promote the nucleophilic attack of a zinc-bound hydroxide ion onto the ceramide amide carbonyl. Furthermore, we present a revised ADIPOR1 crystal structure exhibiting a seven-transmembranedomain architecture that is clearly distinct from that of ADIPOR2. In this structure, no FFA is observed and the ceramide binding pocket and putative zinc catalytic site are exposed to the inner membrane leaflet. ADIPOR1 also possesses intrinsic ceramidase activity, so we suspect that the two distinct structures may represent key steps in the enzymatic activity of ADIPORs. The ceramidase activity is low, however, and further studies will be required to characterize fully the enzymatic parameters and substrate specificity of ADIPORs. These insights into ADIPOR function will enable the structure-based design of potent modulators of these clinically relevant enzymes.
机译：脂联素受体（ADIPOR）是不可或缺的膜蛋白，可通过至少部分介导催化神经酰胺水解产生鞘氨醇和游离脂肪酸（FFA）的细胞神经酰胺酶活性来控制葡萄糖和脂质代谢。两种受体亚型ADIPOR1和ADIPOR2的晶体结构显示出相似的整体7个跨膜结构域结构，其中有较大的空位和7个跨膜结构域2中的锌结合位点。但是，ADIPOR发挥作用的分子机制尚不清楚。在这里，我们描述了结合到FFA分子上的ADIPOR2的晶体结构，并表明ADIPOR2具有固有的基础脂族酰胺酶活性，该活性被脂联素增强。我们还确定了神经酰胺结合的姿势，并提出了使用计算方法的ADIPOR2水解活性的可能机制。在分子动力学模拟中，配位锌的残基侧链迅速重排，以促进结合锌的氢氧根离子对神经酰胺酰胺羰基的亲核攻击。此外，我们提出了一种经过修改的ADIPOR1晶体结构，该结构具有七个跨膜结构域结构，与ADIPOR2明显不同。在这种结构中，未观察到FFA，并且神经酰胺结合袋和推定的锌催化位点暴露于内膜小叶。 ADIPOR1还具有固有的神经酰胺酶活性，因此我们怀疑这两个不同的结构可能代表了ADIPORs酶促活性的关键步骤。然而，神经酰胺酶的活性较低，需要进一步研究以充分表征ADIPOR的酶学参数和底物特异性。对ADIPOR功能的这些了解将使这些临床相关酶的有效调节剂能够进行基于结构的设计。

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  • 来源
    《Nature》 |2017年第7648期|120-123|共4页
  • 作者

    Vasiliauskaite-Brooks Ieva; Sounier Remy; Rochaix Pascal; Bellot Gaetan; Fortier Mathieu; Hoh Francois; De Colibus Luigi; Bechara Cherine; Saied Essa M.; Arenz Christoph; Leyrat Cedric; Granier Sebastien;

  • 作者单位

    Univ Montpellier, CNRS UMR 5203, INSERM U1191, Inst Genom Fonct, F-34094 Montpellier, France;

    Univ Montpellier, CNRS UMR 5203, INSERM U1191, Inst Genom Fonct, F-34094 Montpellier, France;

    Univ Montpellier, CNRS UMR 5203, INSERM U1191, Inst Genom Fonct, F-34094 Montpellier, France;

    Univ Montpellier, CNRS UMR 5203, INSERM U1191, Inst Genom Fonct, F-34094 Montpellier, France;

    Univ Montpellier, CNRS UMR 5203, INSERM U1191, Inst Genom Fonct, F-34094 Montpellier, France;

    Univ Montpellier, CNRS UMR 5048, Ctr Biochim Struct, INSERM 1054, 29 Rue Navacelles, F-34090 Montpellier, France;

    Univ Oxford, Div Struct Biol, Oxford, England;

    Univ Montpellier, CNRS UMR5235, Dynam Interact Membranaires Norm & Patholog, F-34095 Montpellier, France;

    Humboldt Univ, Inst Chem, Brook Taylor Str 2, D-12489 Berlin, Germany|Suez Canal Univ, Fac Sci, Dept Chem, Ismailia 41522, Egypt;

    Humboldt Univ, Inst Chem, Brook Taylor Str 2, D-12489 Berlin, Germany;

    Univ Montpellier, CNRS UMR 5203, INSERM U1191, Inst Genom Fonct, F-34094 Montpellier, France;

    Univ Montpellier, CNRS UMR 5203, INSERM U1191, Inst Genom Fonct, F-34094 Montpellier, France;

  • 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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