ALIX-CHMP4 interactions in the human ESCRT pathway
ALIX-CHMP4 interactions in the human ESCRT pathway
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DOI：
10.1073/pnas.0801567105
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发表时间：
2008-06-03
影响因子：
11.1
通讯作者：
Hill, Christopher P.
中科院分区：
文献类型：
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作者：
McCullough, John;Fisher, Robert D.;Hill, Christopher P.
ESCRT途径在包膜病毒出芽、多泡体形成和胞质分裂期间促进膜分裂事件。为了促进HIV出芽和胞质分裂，阿利克斯蛋白必须结合和募集ESCRT-III复合物的CHMP 4亚基，这反过来又参与了基本的膜重塑功能。在这里，我们报告说，阿利克斯的Bro 1结构域特异性结合到人CHMP 4蛋白（CHMP 4A-C）的C-末端残基。复合物的晶体结构显示，CHMP 4 C-末端肽形成两亲性螺旋，其跨越阿利克斯（Bro 1）的保守凹面结合。ALIX依赖性HIV-1出芽被暴露的阿利克斯（Bro 1）残基突变阻断，这些残基有助于形成CHMP 4识别螺旋（M/L/IxxLxxW）一侧显示的三个必需疏水残基的结合位点。ESCRT-III蛋白的同源CHMP 1 -3类也具有C-末端两亲性螺旋，但在这些情况下，三个疏水残基以L/I/MxxxLxxL间距排列。因此，疏水残基的不同模式提供了允许不同ESCRT-III亚基结合不同ESCRT途径配偶体的“密码”，其中CHMP 1 -3蛋白结合含MIT结构域的蛋白，如VPS 4和Vta 1/LIP 5，CHMP 4蛋白结合含Bro 1结构域的蛋白，如阿利克斯。
The ESCRT pathway facilitates membrane fission events during enveloped virus budding, multivesicular body formation, and cytokinesis. To promote HIV budding and cytokinesis, the ALIX protein must bind and recruit CHMP4 subunits of the ESCRT-III complex, which in turn participate in essential membrane remodeling functions. Here, we report that the Bro1 domain of ALIX binds specifically to C-terminal residues of the human CHMP4 proteins (CHMP4A-C). Crystal structures of the complexes reveal that the CHMP4 C-terminal peptides form amphipathic helices that bind across the conserved concave surface of ALIX(Bro1). ALIX-dependent HIV-1 budding is blocked by mutations in exposed ALIX(Bro1) residues that help contribute to the binding sites for three essential hydrophobic residues that are displayed on one side of the CHMP4 recognition helix (M/L/IxxLxxW). The homologous CHMP1-3 classes of ESCRT-III proteins also have C-terminal amphipathic helices, but, in those cases, the three hydrophobic residues are arrayed with L/I/MxxxLxxL spacing. Thus, the distinct patterns of hydrophobic residues provide a "code" that allows the different ESCRT-III subunits to bind different ESCRT pathway partners, with CHMP1-3 proteins binding MIT domain-containing proteins, such as VPS4 and Vta1/LIP5, and CHMP4 proteins binding Bro1 domain-containing proteins, such as ALIX.