Proteolytic refolding of the HIV-1 capsid protein amino-terminus facilitates viral core assembly
Proteolytic refolding of the HIV-1 capsid protein amino-terminus facilitates viral core assembly
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DOI：
10.1093/emboj/17.6.1555
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发表时间：
1998-03-16
期刊：
影响因子：
11.4
通讯作者：
Sundquist, WI
中科院分区：
文献类型：
--
作者：
von Schwedler, UK;Stemmler, TL;Sundquist, WI
人类免疫缺陷病毒（HIV）在出芽后必须“成熟”成感染性病毒颗粒，病毒成熟需要在基质-衣壳连接处的Gag多聚蛋白的蛋白水解加工，其释放衣壳（CA）结构域以从未成熟病毒的球形蛋白质外壳浓缩成成熟病毒的圆锥形核心。衣壳的氨基末端重新折叠成β-发夹/螺旋结构，该结构通过在加工的氨基末端（Pro 1）和高度保守的天冬氨酸残基（Asp 51）之间形成盐桥而稳定，然后，重新折叠的氨基末端产生了一个新的CA-CA界面，这对于组装浓缩的锥形核心是必不可少的。与该模型一致，我们发现，具有少至四个基质残基融合到其氨基末端的重组衣壳蛋白在体外形成球体，但是去除这些残基会使衣壳氨基末端重折叠并将蛋白质组装从球体重定向到圆柱体。此外，贯穿推定的CA-CA界面的点突变阻断了体外衣壳组装、体内核心组装和病毒感染性。保守的氨基末端衣壳盐桥的破坏也消除了Moloney鼠白血病病毒颗粒的感染性，表明慢病毒和癌病毒通过类似的途径成熟。
After budding, the human immunodeficiency virus (HIV) must 'mature' into an infectious viral particle, Viral maturation requires proteolytic processing of the Gag polyprotein at the matrix-capsid junction, which liberates the capsid (CA) domain to condense from the spherical protein coat of the immature virus into the conical core of the mature virus, We propose that upon proteolysis, the amino-terminal end of the capsid refolds into a beta-hairpin/helix structure that is stabilized by formation of a salt bridge between the processed amino-terminus (Pro1) and a highly conserved aspartate residue (Asp51), The refolded amino-terminus then creates a new CA-CA interface that is essential for assembling the condensed conical core, Consistent with this model, we found that recombinant capsid proteins with as few as four matrix residues fused to their amino-termini formed spheres in vitro, but that removing these residues refolded the capsid amino-terminus and redirected protein assembly from spheres to cylinders, Moreover, point mutations throughout the putative CA-CA interface blocked capsid assembly in vitro, core assembly in vivo and viral infectivity, Disruption of the conserved amino-terminal capsid salt bridge also abolished the infectivity of Moloney murine leukemia viral particles, suggesting that lenti- and onco-viruses mature via analogous pathways.