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首页> 外文期刊>Biochemistry >Alanine Scanning Mutagenesis of HIV-I gp41 Heptad Repeat 1: Insight intothe gp120—gp41 Interactiont
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Alanine Scanning Mutagenesis of HIV-I gp41 Heptad Repeat 1: Insight intothe gp120—gp41 Interactiont

机译：HIV-1 gp41七肽的丙氨酸扫描诱变重复1：深入了解gp120-gp41相互作用

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摘要

On the basis of mutagenesis, biochemical, and structural studies, heptad repeat 1 of HIV gp4l(HRI) I ) has been shown to play numerous critical roles in HIV entry, including interacting with gp120 inprefusion states and interacting with gp41 heptad repeat 2 (HR2) in the fusion state. Moreover, HR I is the siteof therapeutic intervention by enfuviritide, a peptide analogue of HR2. In this study, the functionalimportance of each amino acid residue in gp4l LIR I has been systematically examined by alanine scanningmutagenesis, with subsequent characterization of the mutagenic effects on folding (as measured byincorporation into virions), association with gp120, and membrane fusion. The mutational effects on entrycan be grouped into three classes: (1) wild type (defined as > 40% of wild-type entry), (2) impaired (defined as5-40% of wild-type entry), and (3) nonfunctional (defined as < 5% of wild-type entry). Interestingly, themajority of HR1 mutations (77%) exhibit impaired or nonfunctional entry. Surprisingly, effects of mutationson folding, association, or fusion are not correlated to heptad position; however, folding defects are mostoften found in the N-terminal region of HRI. Moreover, disruption of the gp41—gp120 interaction iscorrelated to the C-terminal region of HR I, suggesting that this region interacts most closely with gp120. Insummary, the sensitivity of gp41 H RI to alanine substitutions suggests that even subtle changes in the localenvironment may severely affect envelope function, thereby strengthening the notion that HR 1 is an attractivesite for therapeutic intervention.
机译：在诱变，生化和结构研究的基础上，已证明HIV gp4l（HRI）I的七肽重复序列1在HIV进入过程中起着许多关键作用，包括与gp120灌注前状态相互作用和与gp41七肽重复序列2（HR2）相互作用。 ）处于融合状态。此外，HR I是enfuviritide（HR2的肽类似物）进行治疗干预的部位。在这项研究中，已通过丙氨酸扫描诱变系统地检查了gp41 LIR I中每个氨基酸残基的功能重要性，随后表征了对折叠的诱变作用（通过掺入病毒体来衡量），与gp120的结合以及膜融合。突变对进入的影响可分为三类：（1）野生型（定义为野生型进入的40％），（2）受损（定义为野生型进入的5-40％）和（3）非功能性的（定义为野生型进入的<5％）。有趣的是，大多数HR1突变（77％）显示出受损或无功能的进入。令人惊讶的是，突变，折叠，缔合或融合的作用与七肽的位置无关。然而，折叠缺陷通常在HRI的N端区域发现。此外，gp41-gp120相互作用的破坏与HR I的C端区域相关，表明该区域与gp120相互作用最紧密。总之，gp41 H RI对丙氨酸替代的敏感性表明，即使局部环境的细微变化也可能严重影响包膜功能，从而强化了HR 1是治疗干预的诱人位点的观念。

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