Mechanism of membrane perturbation by the HIV-1 gp41 membrane-proximal external region and its modulation by cholesterol.
Mechanism of membrane perturbation by the HIV-1 gp41 membrane-proximal external region and its modulation by cholesterol.
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DOI：
10.1016/j.bbamem.2012.06.002
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发表时间：
2012-11
期刊：
影响因子：
--
通讯作者：
Nieva JL
中科院分区：
文献类型：
--
作者：
Ivankin A;Apellániz B;Gidalevitz D;Nieva JL
糖蛋白41膜近端外区（MPER）的膜活性是HIV-1膜融合所必需的。因此，它的抑制作用导致病毒被抗体4E10中和。先前的研究表明，MPER可能通过局部干扰病毒膜在融合过程中起作用，即遵循类似于某些抗菌肽的机制。在这里，我们利用掠射x射线衍射和x射线反射率探讨了MPER如何渗透含有胆固醇的脂质单层（病毒包膜的主要成分）的分子机制。我们的研究表明，螺旋MPER在不影响脂质横向堆积顺序的条件下形成溶解孔。此外，我们观察到富含胆固醇的膜中MPER螺旋占据的表面积增加，这与脂质囊泡中4E10表位的可及性增强有关。因此，我们的数据支持这样的观点，即MPER疏水插入病毒膜产生的曲率在功能上比脂质包装破坏更相关。
Membrane-activity of the glycoprotein 41 membrane-proximal external region (MPER) is required for HIV-1 membrane fusion. Consequently, its inhibition results in viral neutralization by the antibody 4E10. Previous studies suggested that MPER might act during fusion by locally perturbing the viral membrane, i.e., following a mechanism similar to that proposed for certain antimicrobial peptides. Here, we explore the molecular mechanism of how MPER permeates lipid monolayers containing cholesterol, a main component of the viral envelope, using grazing incidence X-ray diffraction and X-ray reflectivity. Our studies reveal that helical MPER forms lytic pores under conditions not affecting the lateral packing order of lipids. Moreover, we observe an increment of the surface area occupied by MPER helices in cholesterol-enriched membranes, which correlates with an enhancement of the 4E10 epitope accessibility in lipid vesicles. Thus, our data support the view that curvature generation by MPER hydrophobic insertion into the viral membrane is functionally more relevant than lipid packing disruption.
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