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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structural basis of oligomerization in septin-like GTPase of immunity-associated protein 2 (GIMAP2)
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Structural basis of oligomerization in septin-like GTPase of immunity-associated protein 2 (GIMAP2)

机译：免疫相关蛋白2（GIMAP2）的Septin样GTPase中寡聚的结构基础

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摘要

GTPases of immunity-associated proteins (GIMAPs) are a distinctive family of GTPases, which control apoptosis in lymphocytes and play a central role in lymphocyte maturation and lymphocyte-associated diseases. To explore their function and mechanism, we determined crystal structures of a representative member, GIMAP2, in different nucleotide-loading and oligomerization states. Nucleo-tide-free and GDP-bound GIMAP2 were monomeric and revealed a guanine nucleotide-binding domain of the TRAFAC (translation factor associated) class with a unique amphipathic helix α7 packing against switch II. In the absence of α7 and the presence of GTP, GIMAP2 oligomerized via two distinct interfaces in the crystal. GTP-induced stabilization of switch I mediates dimerization across the nucleotide-binding site, which also involves the GIMAP specificity motif and the nucleotide base. Structural rearrangements in switch II appear to induce the release of α7 allowing oligomerization to proceed via a second interface. The unique architecture of the linear oligomer was confirmed by mutagenesis. Furthermore, we showed a function for the GIMAP2 oligomer at the surface of lipid droplets. Although earlier studies indicated that GIMAPs are related to the septins, the current structure also revealed a strikingly similar nucleotide coordination and dimerization mode as in the dynamin GTPase. Based on this, we reexamined the relationships of the septin- and dynamin-like GTPases and demonstrate that these are likely to have emerged from a common membrane-associated dimerizing ancestor. This ancestral property appears to be critical for the role of GIMAPs as nucleotide-regu-lated scaffolds on intracellular membranes.
机译：免疫相关蛋白（GIMAPs）的GTPases是GTPases的一个独特家族，它们控制淋巴细胞的凋亡，并在淋巴细胞成熟和淋巴细胞相关疾病中发挥重要作用。为了探索它们的功能和机理，我们确定了具有代表性的成员GIMAP2的晶体结构，处于不同的核苷酸加载和低聚状态。无核苷酸和GDP结合的GIMAP2是单体，并显示出TRAFAC（翻译因子相关）类的鸟嘌呤核苷酸结合结构域，具有针对开关II的独特的两亲性螺旋α7堆积。在没有α7和GTP的情况下，GIMAP2通过晶体中的两个不同界面低聚。 GTP诱导的开关I的稳定介导了跨核苷酸结合位点的二聚化，这也涉及GIMAP特异性基序和核苷酸碱基。开关II中的结构重排似乎诱导α7的释放，从而允许通过第二界面进行低聚。通过诱变证实了线性低聚物的独特结构。此外，我们在脂质液滴表面显示了GIMAP2低聚物的功能。尽管较早的研究表明GIMAPs与Septins有关，但目前的结构也显示出与动态GTPase相似的核苷酸配位和二聚化模式。基于此，我们重新检查了类似Septin和dynamin的GTPases的关系，并证明这些很可能是从常见的膜相关二聚祖先中出现的。这种祖先性质对于GIMAPs作为细胞内膜上核苷酸调控的支架的作用似乎至关重要。

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    David Schwefel; Chris Froehlich; Jenny Eichhorst; Burkhard Wiesner; Joachim Behlke; L. Aravind; Oliver Daumke;

  • 作者单位

    Max-Delbrueck-Centrum fuer Molekulare Medizin, Kristallographie, Robert-Roessle-Strasse 10, 13125 Berlin, Germany,lnstitut fuer Chemie und Biochemie,Freie Universitat Berlin, Takustrasse 3, 14195 Berlin, Germany;

    Max-Delbrueck-Centrum fuer Molekulare Medizin, Kristallographie, Robert-Roessle-Strasse 10, 13125 Berlin, Germany,lnstitut fuer Chemie und Biochemie,Freie Universitat Berlin, Takustrasse 3, 14195 Berlin, Germany;

    Leibniz-lnstitut fuer Molekulare Pharmakologie, Robert-Rossle-Strasse 10, 13125 Berlin,Germany;

    Leibniz-lnstitut fuer Molekulare Pharmakologie, Robert-Rossle-Strasse 10, 13125 Berlin,Germany;

    Max-Delbrueck-Centrum fuer Molekulare Medizin, Kristallographie, Robert-Roessle-Strasse 10, 13125 Berlin, Germany;

    National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894;

    Max-Delbrueck-Centrum fuer Molekulare Medizin, Kristallographie, Robert-Roessle-Strasse 10, 13125 Berlin, Germany,Institut fur Medizinische Physik und Biophysik, Charite, Ziegelstrasse 5-9, 10117 Berlin, Germany;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    G protein; protein structure;

    机译：G蛋白;蛋白质结构;

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