Nature2014-06-26 7:03 PM

HIV-1与其制约因子SAMHD1之间的关系 Structural basis of lentiviral subversion of a cellular protein degradation pathway

论文摘要 

SAMHD1是人体细胞中产生的一种酶,起针对“人免疫缺陷病毒-1”(HIV-1)的制约因子的作用,阻断病毒对骨髓细胞和CD4+ T细胞的感染。该病毒对抗“辅助蛋白”Vpx,后者以SAMHD1为目标来使蛋白酶体降解。现在,Ian Taylor及同事提供了显示Vpx怎样将SAMHD1吸引到细胞的“泛素化”机构中去的一个结构。由Vpx与E3连接酶基质转接蛋白DCAF1 和SAMHD1一起形成的一个三元复合物的这一晶体结构显示,Vpx包裹在DCAF1周围,改变其形状,使其能够通过它的C-端点来吸收SAMHD1。

Abstract 

Lentiviruses contain accessory genes that have evolved to counteract the effects of host cellular defence proteins that inhibit productive infection. One such restriction factor, SAMHD1, inhibits human immunodeficiency virus (HIV)-1 infection of myeloid-lineage cells as well as resting CD4+ T cells by reducing the cellular deoxynucleoside 5′-triphosphate (dNTP) concentration to a level at which the viral reverse transcriptase cannot function. In other lentiviruses, including HIV-2 and related simian immunodeficiency viruses (SIVs), SAMHD1 restriction is overcome by the action of viral accessory protein x (Vpx) or the related viral protein r (Vpr) that target and recruit SAMHD1 for proteasomal degradation. The molecular mechanism by which these viral proteins are able to usurp the host cell’s ubiquitination machinery to destroy the cell’s protection against these viruses has not been defined. Here we present the crystal structure of a ternary complex of Vpx with the human E3 ligase substrate adaptor DCAF1 and the carboxy-terminal region of human SAMHD1. Vpx is made up of a three-helical bundle stabilized by a zinc finger motif, and wraps tightly around the disc-shaped DCAF1 molecule to present a new molecular surface. This adapted surface is then able to recruit SAMHD1 via its C terminus, making it a competent substrate for the E3 ligase to mark for proteasomal degradation. The structure reported here provides a molecular description of how a lentiviral accessory protein is able to subvert the cell’s normal protein degradation pathway to inactivate the cellular viral defence system.

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