Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
Proc Natl Acad Sci U S A. 2012 Nov 6;109(45):18372-7. doi: 10.1073/pnas.1210903109. Epub 2012 Oct 22.
Tripartite motif protein isoform 5 alpha (TRIM5α) is a potent antiviral protein that restricts infection by HIV-1 and other retroviruses. TRIM5α recognizes the lattice of the retrovirus capsid through its B30.2 (PRY/SPRY) domain in a species-specific manner. Upon binding, TRIM5α induces premature disassembly of the viral capsid and activates the downstream innate immune response. We have determined the crystal structure of the rhesus TRIM5α PRY/SPRY domain that reveals essential features for capsid binding. Combined cryo-electron microscopy and biochemical data show that the monomeric rhesus TRIM5α PRY/SPRY, but not the human TRIM5α PRY/SPRY, can bind to HIV-1 capsid protein assemblies without causing disruption of the capsid. This suggests that the PRY/SPRY domain alone constitutes an important pattern-sensing component of TRIM5α that is capable of interacting with viral capsids of different curvatures. Our results provide molecular insights into the mechanisms of TRIM5α-mediated retroviral restriction.
三结构域蛋白 5 型异构体 5α（TRIM5α）是一种有效的抗病毒蛋白，可限制 HIV-1 和其他逆转录病毒的感染。TRIM5α 通过其 B30.2（PRY/SPRY）结构域以物种特异性方式识别逆转录病毒衣壳的晶格。结合后，TRIM5α 诱导病毒衣壳过早解体并激活下游先天免疫反应。我们已经确定了恒河猴 TRIM5α PRY/SPRY 结构域的晶体结构，揭示了衣壳结合的基本特征。结合冷冻电镜和生化数据表明，单体恒河猴 TRIM5α PRY/SPRY，但不是人 TRIM5α PRY/SPRY，可与 HIV-1 衣壳蛋白组装结合，而不会破坏衣壳。这表明 PRY/SPRY 结构域本身构成了 TRIM5α 的一个重要模式感应组件，能够与不同曲率的病毒衣壳相互作用。我们的结果为 TRIM5α 介导的逆转录病毒限制的机制提供了分子见解。
