A small loop in the capsid protein of Moloney murine leukemia virus controls assembly of spherical cores
A small loop in the capsid protein of Moloney murine leukemia virus controls assembly of spherical cores
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DOI：
10.1128/jvi.80.6.2884-2893.2006
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发表时间：
2006-03-01
影响因子：
5.4
通讯作者：
Singh, IR
中科院分区：
文献类型：
--
作者：
Auerbach, MR;Brown, KR;Singh, IR
我们在Moloney小鼠白血病病毒(MoLV)的Gag蛋白中发现了一个新的结构域，该结构域对球形核心的形成非常重要。对衣壳蛋白(CA)N末端区域18个插入突变的分析发现，有3个在病毒组装和释放方面存在严重缺陷。产生这些突变体的细胞的透射电子显微镜显示，Gag蛋白在质膜上组装成大的、扁平的或圆顶状的斑块。没有形成球状核心，也没有释放病毒颗粒。这个晚期的组装/释放块被野生型病毒部分挽救。这三个突变都定位于CA的ET-螺旋4和5之间的小环，类似于人类免疫缺陷病毒I型CA的亲环素A结合环。在MLV CA六角形的X射线结构中，这个环位于六角体的外围。这个环中突变的表型表明，GAG平面晶格的形成不受环中突变的阻碍。然而，这些平面结构没有向球形结构发展，这表明这个环的突变可能会阻止五聚体或稳定的五聚体-六聚体相互作用的形成，这对形成封闭的球形核心是必不可少的。CA中的这个区域集中在一个小环的少数残基上，可能为逆转录病毒疾病提供一个新的治疗靶点。
We report the identification of a novel domain in the Gag protein of Moloney murine leukemia virus (MoLV) that is important for the formation of spherical cores. Analysis of 18 insertional mutations in the N-terminal domain of the capsid protein (CA) identified 3 that were severely defective for viral assembly and release. Transmission electron microscopy of cells producing these mutants showed assembly of Gag proteins in large, flat or dome-shaped patches at the plasma membrane. Spherical cores were not formed, and viral particles were not released. This late assembly/release block was partially rescued by wild-type virus. All three mutations localized to the small loop between et-helices 4 and 5 of CA, analogous to the cyclophilin A-binding loop of human immunodeficiency virus type I CA. In the X-ray structure of the hexameric form of MLV CA, this loop is located at the periphery of the hexamer. The phenotypes of mutations in this loop suggest that formation of a planar lattice of Gag is unhindered by mutations in the loop. However, the lack of progression of these planar structures to spherical ones suggests that mutations in this loop may prevent formation of pentamers or of stable pentamer-hexamer interactions, which are essential for the formation of a closed, spherical core. This region in CA, focused to a few residues of a small loop, may offer a novel therapeutic target for retroviral diseases.