Characterization of conserved motifs in HIV-1 Vif required for APOBEC3G and APOBEC3F interaction
Characterization of conserved motifs in HIV-1 Vif required for APOBEC3G and APOBEC3F interaction
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DOI：
10.1016/j.jmb.2008.06.061
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发表时间：
2008-09-12
影响因子：
5.6
通讯作者：
Yu, Xiao-Fang
中科院分区：
文献类型：
--
作者：
He, Zhiwen;Zhang, Wenyan;Yu, Xiao-Fang
载脂蛋白 B mRNA 编辑催化多肽样 3G（APOBEC3G 或 A3G）和相关胞苷脱氨酶如载脂蛋白 B mRNA 编辑催化多肽样 3F（APOBEC3F 或 A3F）是逆转录病毒的有效抑制剂。传染性人类免疫缺陷病毒 (HIV)-1 的形成需要 Vif 抑制多种胞苷脱氨酶。 HIV-1。 Vif 通过招募 Cullin5、ElonginB 和 ElonginC E3 泛素连接酶诱导靶蛋白多泛素化和蛋白酶体介导的降解，通过常见机制抑制各种 APOBEC3 蛋白。 Vif 中介导 APOBEC3 识别的结构域尚未得到充分表征。在本研究中，我们在HIV-1 Vif中鉴定了VxIPLx(4-5)Lx phi X(2)YWxL基序，该基序是Vif和A3G之间的有效相互作用、Vif介导的A3G降解和病毒粒子排除以及A3G抗病毒活性的功能性抑制所必需的。 HIV-1 Vif 的氨基酸 52 至 72（包括 VxIPLx(4-5)Lx phi x(2)YWxL 基序）单独可以介导与 A3G 的相互作用，并且这种相互作用被该区域中两个疏水性氨基酸的突变所消除。我们还观察到 Vif 突变体对 A3G 无效，但它保留了与 Cullin5-E3 泛素复合物和 A3G 相互作用的能力，表明与 A3G 的相互作用是必要的，但不足以抑制其抗病毒功能。与先前鉴定的 HIV-1 Vif 氨基酸 40 至 44 的基序（仅对 A3G 抑制很重要）不同，VxIPLx(4-5)Lx phi x(2)yWxL 基序对于有效的 A3F 相互作用和抑制也是必需的。另一方面，发现 HIV-1 Vif 氨基酸 74 至 79 的另一个基序 TGERxW 对于 A3F 相互作用和抑制非常重要。 VxIPLx(4-5)Lx phi x(2)YWxL 和 TGERxW 基序在 HIV-1、HIV-2 和各种猿猴免疫缺陷病毒 Vif 蛋白中高度保守。我们的数据表明，灵长类慢病毒 Vif 分子通过保守的结构特征识别其自体 APOBEC3 蛋白，这些保守的结构特征代表了新型抑制剂开发的有吸引力的靶标。由爱思唯尔有限公司出版
Apolipoprotein B mRNA-editing catalytic polypeptide-like 3G (APOBEC3G, or A3G) and related cytidine deaminases such as apolipoprotein B mRNA-editing catalytic polypeptide-like 3F (APOBEC3F, or A3F) are potent inhibitors of retroviruses. Formation of infectious human immunodeficiency virus (HIV)-1 requires suppression of multiple cytidine deaminases by Vif. HIV-1. Vif suppresses various APOBEC3 proteins through a common mechanism by recruiting Cullin5, ElonginB, and ElonginC E3 ubiquitin ligase to induce target protein polyubiquitination and proteasome-mediated degradation. Domains in Vif that mediate APOBEC3 recognition have not been fully characterized. In the present study, we identified a VxIPLx(4-5)Lx phi X(2)YWxL motif in HIV-1 Vif, which is required for efficient interaction between Vif and A3G, Vif-mediated A3G degradation and virion exclusion, and functional suppression of the A3G antiviral activity. Amino acids 52 to 72 of HIV-1 Vif (including the VxIPLx(4-5)Lx phi x(2)YWxL motif) alone could mediate interaction with A3G, and this interaction was abolished by mutations of two hydrophobic amino acids in this region. We have also observed that a Vif mutant was ineffective against A3G, yet it retained the ability to interact with Cullin5-E3 ubiquitin complex and A3G, suggesting that interaction with A3G is necessary but not sufficient to inhibit its antiviral function. Unlike the previously identified motif of HIV-1 Vif amino acids 40 to 44, which is only important for A3G suppression, the VxIPLx(4-5)Lx phi x(2)yWxL motif is also required for efficient A3F interaction and suppression. On the other hand, another motif, TGERxW, of HIV-1 Vif amino acids 74 to 79 was found to be mainly important for A3F interaction and inhibition. Both the VxIPLx(4-5)Lx phi x(2)YWxL and TGERxW motifs are highly conserved among HIV-1, HIV-2, and various simian immunodeficiency virus Vif proteins. Our data suggest that primate lentiviral Vif molecules recognize their autologous APOBEC3 proteins through conserved structural features that represent attractive targets for the development of novel inhibitors. Published by Elsevier Ltd.