Institute for Protein Research, Osaka University, Yamadaoka 3-2, Suita, Osaka, 565-0871, Japan.
Biophysics Program and Department of Chemistry, The University of Michigan, Ann Arbor, Michigan, 48109-1055.
Protein Sci. 2018 Jul;27(7):1151-1165. doi: 10.1002/pro.3395. Epub 2018 Mar 14.
Misfolding and amyloid aggregation of intrinsically disordered proteins (IDPs) are implicated in a variety of diseases. Studies have shown that membrane plays important roles on the formation of intermediate structures of IDPs that can initiate (and/or speed-up) amyloid aggregation to form fibers. The process of amyloid aggregation also disrupts membrane to cause cell death in amyloid diseases like Alzheimer's disease and type-2 diabetes. On the other hand, recent studies reported the membrane fusion properties of amyloid fibers. Remarkably, amyloid-fibril formation by short peptide fragments of highly abundant prostatic acidic-phosphatase (PAP) in human semen and are capable of boosting the rate of HIV infection up to 400,000-fold during sexual contact. Unlike the least toxic fully matured fibers of most amyloid proteins, the semen-derived enhancer of virus infection (SEVI) amyloid-fibrils of PAP peptide fragments are highly potent in rendering the maximum rate of HIV infection. This unusual property of amyloid fibers has witnessed increasing number of studies on the biophysical aspects of fiber formation and fiber-membrane interactions. NMR studies have reported a highly disordered partial helical structure in a membrane environment for the intrinsically disordered PAP peptide that promotes the fusion of the viral membrane with that of host cells. The purpose of this review article is to unify and integrate biophysical and immunological research reported in the previous studies on SEVI. Specifically, amyloid aggregation, dramatic HIV infection enhancing properties, membrane fusion properties, high resolution NMR structure, and approaches to eliminate the enhancement of HIV infection of SEVI peptides are discussed.
错误折叠和淀粉样蛋白聚集的无规卷曲蛋白质（IDPs）与多种疾病有关。研究表明，膜在 IDPs 中间结构的形成中起着重要作用，这些中间结构可以启动（和/或加速）淀粉样蛋白聚集形成纤维。淀粉样蛋白聚集的过程也会破坏膜，导致阿尔茨海默病和 2 型糖尿病等淀粉样蛋白疾病的细胞死亡。另一方面，最近的研究报道了淀粉样蛋白纤维的膜融合特性。值得注意的是，人类精液中高丰度前列腺酸性磷酸酶（PAP）的短肽片段形成淀粉样纤维，能够在性接触中使 HIV 感染率提高多达 400,000 倍。与大多数淀粉样蛋白纤维中毒性最小的完全成熟纤维不同，PAP 肽片段的精液衍生病毒感染增强因子（SEVI）淀粉样纤维能够最大限度地提高 HIV 感染率。淀粉样纤维的这种不寻常特性见证了越来越多的关于纤维形成和纤维-膜相互作用的生物物理方面的研究。NMR 研究报告称，在膜环境中，无规卷曲的 PAP 肽具有高度无序的部分螺旋结构，可促进病毒膜与宿主细胞膜的融合。本文综述的目的是将以前关于 SEVI 的研究中报道的生物物理和免疫学研究统一起来并进行整合。具体来说，讨论了淀粉样蛋白聚集、显著增强 HIV 感染的特性、膜融合特性、高分辨率 NMR 结构以及消除 SEVI 肽增强 HIV 感染的方法。
