Antiretroviral activity of TRIM5alpha

描述（由申请人提供）：一些哺乳动物，包括灵长类动物，表达显性限制因子，在病毒复制的早期阶段阻断某些逆转录病毒的感染。TRIM 51或在某些物种中称为TRIMCyp的TRIM 5-亲环蛋白A融合蛋白通过在其进入宿主细胞质时结合逆转录病毒衣壳来介导这些早期阻断。TRIM 51是三重基序（TRIM）蛋白家族的成员，并且包含RING、B-box 2、卷曲螺旋和B30.2/SPRY结构域。卷曲螺旋有助于TRIM 51二聚化; B30.2/SPRY结构域有助于衣壳识别。RING和B-box 2结构域在TRIM 51介导的逆转录病毒限制中的功能尚不清楚。这些结构域有助于逆转录病毒限制的效力，这被认为涉及加速病毒衣壳的脱壳。这项竞争性更新申请的总体目标是了解TRIM 51介导的逆转录病毒限制的分子机制，并确定单个TRIM 51结构域和衣壳元件在病毒识别和抑制中的作用。本研究的具体目的是：1）研究TRIM 51 B-box 2结构域在逆转录病毒限制中的作用; 2）研究TRIM 51 RING结构域的E3泛素连接酶活性对逆转录病毒限制的贡献; 3）测试TRIM 51介导的逆转录病毒限制的机制模型;和4）确定逆转录病毒衣壳的变化如何影响与TRIM 51和宿主细胞辅因子如亲环素A的相互作用。

DESCRIPTION (provided by applicant): Some mammals, including primates, express dominant restriction factors that block the infection of certain retroviruses during the early phase of virus replication. TRIM51 or, in some species, a TRIM5- cyclophilin A fusion protein called TRIMCyp, mediates these early blocks by binding the retroviral capsid as it enters the host cell cytoplasm. TRIM51 is a member of the tripartite motif (TRIM) family of proteins and contains RING, B-box 2, coiled coil and B30.2/SPRY domains. The coiled coil contributes to TRIM51 dimerization; the B30.2/SPRY domain contributes to capsid recognition. The functions of the RING and B-box 2 domains in TRIM51-mediated retroviral restriction are less well understood. These domains contribute to the potency of retrovirus restriction, which is thought to involve the accelerated uncoating the viral capsid. The overall goal of this competing renewal application is to understand the molecular mechanism of TRIM51- mediated retrovirus restriction and to define the roles of individual TRIM51 domains and capsid elements in virus recognition and inhibition. The specific aims of this proposal are: 1) To investigate the role of the TRIM51 B-box 2 domain in retrovirus restriction; 2) To investigate the contribution of the E3 ubiquitin ligase activity of the TRIM51 RING domain to retrovirus restriction; 3) To test mechanistic models of TRIM51-mediated retrovirus restriction; and 4) To define how changes in the retroviral capsid influence interaction with TRIM51 and host cell cofactors such as cyclophilin A.