Helical Conformation of the SEVI Precursor Peptide PAP248-286, a Dramatic Enhancer of HIV Infectivity, Promotes Lipid Aggregation and Fusion
Helical Conformation of the SEVI Precursor Peptide PAP248-286, a Dramatic Enhancer of HIV Infectivity, Promotes Lipid Aggregation and Fusion
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DOI：
10.1016/j.bpj.2009.08.034
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发表时间：
2009-11-04
影响因子：
3.4
通讯作者：
Ramamoorthy, Ayyalusamy
中科院分区：
文献类型：
--
作者：
Brender, Jeffrey R.;Hartman, Kevin;Ramamoorthy, Ayyalusamy
在先前的体内研究中，发现由普遍存在的肽类人精液（精液衍生的病毒感染增强剂（SEVI））形成的淀粉样蛋白纤维显著增强HIV病毒的感染性（通过某些测量，3-5个数量级）。为了补充这些研究，我们对PAP（248-286）（SEVI的最活性前体）和其他聚阳离子聚合物进行了体外测定，以研究PAP（248-286）促进与脂质双层相互作用的物理机制。在酸性（但不是中性）pH下，新鲜溶解的PAP（248-286）催化在各种膜组合物中形成大的脂质絮凝物，这可能与促进阴道环境中的对流运输而不是通过随机布朗运动的运输有关。此外，PAP（248-286）本身是促融合的，并以这样一种方式削弱膜的完整性，从而可能促进HIV gp 41蛋白的融合。PAP（248-286）的α-螺旋构象平行于膜表面，通过屏蔽当两个膜紧密接触时发生的静电排斥而促进膜之间的桥接相互作用。这表明螺旋构象的单体或小寡聚体形式的SEVI与脂质膜的非特异性结合可能是SEVI增强HIV病毒感染性的另一种机制。
In previous in vivo studies, amyloid fibers formed from a peptide ubiquitous inhuman seminal fluid (semen-derived enhancer of viral infection (SEVI)) were found to dramatically enhance the infectivity of the HIV virus (3-5 orders of magnitude by some measures). To complement those studies, we performed in vitro assays of PAP(248-286), the most active precursor to SEVI, and other polycationic polymers to investigate the physical mechanisms by which the PAP(248-286) promotes the interaction with lipid bilayers. At acidic (but not at neutral) pH, freshly dissolved PAP(248-286) catalyzes the formation of large lipid flocculates in a variety of membrane compositions, which may be linked to the promotion of convective transport in the vaginal environment rather than transport by a random Brownian motion. Furthermore, PAP(248-286) is itself fusiogenic and weakens the integrity of the membrane in such a way that may promote fusion by the HIV gp41 protein. An alpha-helical conformation of PAP(248-286), lying parallel to the membrane surface, is implicated in promoting bridging interactions between membranes by the screening of the electrostatic repulsion that occurs when two membranes are brought into close contact. This suggests that nonspecific binding of monomeric or small oligomeric forms of SEVI in a helical conformation to lipid membranes may be an additional mechanism by which SEVI enhances the infectivity of the HIV virus.