NMR structure in a membrane environment reveals putative amyloidogenic regions of the SEVI precursor peptide PAP(248-286).
NMR structure in a membrane environment reveals putative amyloidogenic regions of the SEVI precursor peptide PAP(248-286).
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DOI：
10.1021/ja908170s
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发表时间：
2009-12-16
影响因子：
15
通讯作者：
Ramamoorthy, Ayyalusamy
中科院分区：
文献类型：
--
作者：
Nanga, Ravi P. R.;Brender, Jeffrey R.;Vivekanandan, Subramanian;Popovych, Nataliya;Ramamoorthy, Ayyalusamy
精液是全世界艾滋病毒传播的主要媒介。最近，从精液中分离出一种肽片段（PAP248-286），它可以使 HIV 的感染性显着增强四到五个数量级。 PAP248-286 似乎通过形成称为 SEVI 的淀粉样纤维来增强 HIV 感染，人们认为 SEVI 可以通过桥接病毒粒子和宿主细胞膜之间的相互作用来增强病毒的附着。我们使用 SDS 胶束中的 NMR 光谱解析了 SEVI 前体 PAP248-286 的原子级分辨率结构，该胶束作为模型膜系统。 PAP248-286 不会像大多数淀粉样蛋白那样破坏膜，而是与胶束表面表面结合，这与其他通常渗透到膜核心的膜破坏性淀粉样肽相反。 PAP248-286 的结构与大多数淀粉样肽不同，因为 PAP248-286 与胶束表面结合时大部分是无序的，这与大多数淀粉样蛋白通常发现的 α 螺旋结构相反。 SEVI肽的高度无序性质可以解释SEVI淀粉样纤维增强HIV感染的独特能力，因为部分无序的淀粉样纤维比致密的淀粉样纤维具有更大的病毒捕获半径。新生结构的两个区域（来自 V262-H270 的 α 螺旋和来自 S279-L283 的动态 α/310 螺旋）与高度淀粉样蛋白生成序列的预测相匹配，并且可能充当聚集和淀粉样蛋白原纤维形成的核。这里提出的结构可用于 SEVI 淀粉样蛋白形成和病毒感染增强的诱变研究的合理设计。
Semen is the main vector for HIV transmission worldwide. Recently, a peptide fragment (PAP248–286) has been isolated from seminal fluid that dramatically enhances HIV infectivity by up to four to five orders of magnitude. PAP248–286 appears to enhance HIV infection by forming amyloid fibers known as SEVI, which are believed to enhance the attachment of the virus by bridging interactions between virion and host-cell membranes. We have solved the atomic-level resolution structure of the SEVI precursor PAP248–286 using NMR spectroscopy in SDS micelles, which serve as a model membrane system. PAP248–286, which does not disrupt membranes like most amyloid proteins, binds superficially to the surface of the micelle, in contrast to other membrane-disruptive amyloid peptides that generally penetrate into the core of the membrane. The structure of PAP248–286 is unlike most amyloid peptides in that PAP248–286 is mostly disordered when bound to the surface of the micelle, as opposed to the α-helical structures typically found of most amyloid proteins. The highly disordered nature of the SEVI peptide may explain the unique ability of SEVI amyloid fibers to enhance HIV infection as partially disordered amyloid fibers will have a greater capture radius for the virus than compact amyloid fibers. Two regions of nascent structure (an α-helix from V262-H270 and a dynamic α/310 helix from S279-L283) match the prediction of highly amyloidogenic sequences and may serve as nuclei for aggregation and amyloid fibril formation. The structure presented here can be used for the rational design of mutagenesis studies on SEVI amyloid formation and viral infection enhancement.
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