Hexagonal assembly of a restricting TRIM5α protein
Hexagonal assembly of a restricting TRIM5α protein
复制标题
DOI：
10.1073/pnas.1013426108
复制
发表时间：
2011-01-11
影响因子：
11.1
通讯作者：
Yeager, Mark
中科院分区：
文献类型：
--
作者：
Ganser-Pornillos, Barbie K.;Chandrasekaran, Viswanathan;Yeager, Mark
TRIM5 α蛋白是一种限制性因子，通过结合进入的病毒衣壳，加速其解离，防止病毒基因组的逆转录，保护哺乳动物细胞免受逆转录病毒感染。单个TRIM5亚型通常可以保护细胞免受多种逆转录病毒的侵害，例如恒河猴TRIM5 α及其变体TRIM5- 21r，它们识别HIV-1以及几种远亲逆转录病毒。尽管衣壳识别尚未完全了解，但先前的研究表明，二聚体TRIM5 α的c端SPRY/B30.2结构域直接与病毒衣壳结合，并且高阶TRIM5 α寡聚化似乎有助于衣壳识别的效率。在这里，我们报道重组TRIM5-21R自发组装成二维准晶六边形晶格，包括开放的六面环。TRIM5- 21r组装不需要c端SPRY结构域，但确实需要蛋白二聚化和先前涉及TRIM5 α限制和高阶组装的B-box 2残基（Arg121）。此外，TRIM5-21R通过与模拟病毒衣壳表面的HIV-1 CA蛋白的六边形阵列结合而促进组装。因此，我们提出TRIM5 α蛋白已经进化到通过组装一个可变形的六边形支架来限制一系列不同的逆转录病毒，该支架定位衣壳结合域以匹配衣壳表面晶格的对称性和间距。因此，衣壳识别涉及直接结合相互作用、亲和效应、模板组装和晶格互补的协同组合。
TRIM5 alpha proteins are restriction factors that protect mammalian cells from retroviral infections by binding incoming viral capsids, accelerating their dissociation, and preventing reverse transcription of the viral genome. Individual TRIM5 isoforms can often protect cells against a broad range of retroviruses, as exemplified by rhesus monkey TRIM5 alpha and its variant, TRIM5-21R, which recognize HIV-1 as well as several distantly related retroviruses. Although capsid recognition is not yet fully understood, previous work has shown that the C-terminal SPRY/B30.2 domain of dimeric TRIM5 alpha binds directly to viral capsids, and that higher-order TRIM5 alpha oligomerization appears to contribute to the efficiency of capsid recognition. Here, we report that recombinant TRIM5-21R spontaneously assembled into two-dimensional paracrystalline hexagonal lattices comprising open, six-sided rings. TRIM5-21R assembly did not require the C-terminal SPRY domain, but did require both protein dimerization and a B-box 2 residue (Arg121) previously implicated in TRIM5 alpha restriction and higher-order assembly. Furthermore, TRIM5-21R assembly was promoted by binding to hexagonal arrays of the HIV-1 CA protein that mimic the surface of the viral capsid. We therefore propose that TRIM5 alpha proteins have evolved to restrict a range of different retroviruses by assembling a deformable hexagonal scaffold that positions the capsid-binding domains to match the symmetry and spacing of the capsid surface lattice. Capsid recognition therefore involves a synergistic combination of direct binding interactions, avidity effects, templated assembly, and lattice complementarity.