Ivanov Dmitri, Tsodikov Oleg V, Kasanov Jeremy, Ellenberger Tom, Wagner Gerhard, Collins Tucker
Department of Pathology, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4353-8. doi: 10.1073/pnas.0609477104. Epub 2007 Mar 5.
Assembly of the HIV and other retroviruses is primarily driven by the oligomerization of the Gag polyprotein, the major viral structural protein capable of forming virus-like particles even in the absence of all other virally encoded components. Several critical determinants of Gag oligomerization are located in the C-terminal domain of the capsid protein (CA-CTD), which encompasses the most conserved segment in the highly variable Gag protein called the major homology region (MHR). The CA-CTD is thought to function as a dimerization module, although the existing model of CA-CTD dimerization does not readily explain why the conserved residues of the MHR are essential for retroviral assembly. Here we describe an x-ray structure of a distinct domain-swapped variant of the HIV-1 CA-CTD dimer stabilized by a single amino acid deletion. In the domain-swapped structure, the MHR-containing segment forms a major part of the dimerization interface, providing a structural mechanism for the enigmatic function of the MHR in HIV assembly. Our observations suggest that swapping of the MHR segments of adjacent Gag molecules may be a critical intermediate in retroviral assembly.
HIV及其他逆转录病毒的组装主要由Gag多蛋白的寡聚化驱动，Gag多蛋白是主要的病毒结构蛋白，即使在没有所有其他病毒编码成分的情况下也能形成病毒样颗粒。Gag寡聚化的几个关键决定因素位于衣壳蛋白（CA-CTD）的C末端结构域，该结构域包含Gag蛋白高度可变区域中最保守的片段，称为主要同源区域（MHR）。尽管现有的CA-CTD二聚化模型不能轻易解释为什么MHR的保守残基对逆转录病毒组装至关重要，但CA-CTD被认为起着二聚化模块的作用。在此，我们描述了一种通过单个氨基酸缺失稳定的HIV-1 CA-CTD二聚体的独特结构域交换变体的X射线结构。在结构域交换结构中，包含MHR的片段构成了二聚化界面的主要部分，为MHR在HIV组装中的神秘功能提供了一种结构机制。我们的观察结果表明，相邻Gag分子的MHR片段交换可能是逆转录病毒组装中的一个关键中间体。
