Identification of a common sphingolipid-binding domain in Alzheimer, prion, and HIV-1 proteins
Identification of a common sphingolipid-binding domain in Alzheimer, prion, and HIV-1 proteins
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DOI：
10.1074/jbc.m111679200
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发表时间：
2002-03-29
影响因子：
4.8
通讯作者：
Fantini, J
中科院分区：
文献类型：
--
作者：
Mahfoud, R;Garmy, N;Fantini, J
人免疫缺陷病毒（HIV）-1表面包膜糖蛋白gp 120的V3环是一个鞘脂结合结构域，介导HIV-1与质膜微区（筏）的连接。HIV-1融合需要鞘脂诱导的gp 120构象变化。半乳糖神经酰胺和鞘磷脂已被检测到高度纯化的制备朊病毒棒，这表明朊病毒蛋白（PrP）可能与选定的鞘脂相互作用。此外，已观察到阿尔茨海默氏症β-淀粉样肽的主要构象转变后，与含鞘脂的膜相互作用。结构相似性搜索与组合延伸的方法揭示了一个W样结构域的存在下，在人类朊病毒蛋白PrP和阿尔茨海默氏症β-淀粉样肽。在每种情况下，合成肽来自预测的W样结构域被发现与单分子膜的半乳糖神经酰胺和鞘磷脂在空气-水界面。PrP的W样结构域是一个二硫键连接的环（Cys（179）- Cys（214）），包括与家族性Creutzfeldt-Jakob病相关的E200 K突变位点。该突变消除了鞘磷脂识别。在gp 120、PrP和P-淀粉样肽中识别出一个共同的鞘脂结合基序，强调了脂筏在HIV-1、阿尔茨海默病和朊病毒疾病发病机制中的作用，并可能提供新的治疗策略。
The V3 loop of the human immunodeficiency virus (HIV)-1 surface envelope glycoprotein gp120 is a sphingolipid-binding domain mediating the attachment of HIV-1 to plasma membrane microdomains (rafts). Sphingolipid-induced conformational changes in gp120 are required for HIV-1 fusion. Galactosylceramide and sphingomyelin have been detected in highly purified preparations of prion rods, suggesting that the prion protein (PrP) may interact with selected sphingolipids. Moreover, a major conformational transition of the Alzheimer beta-amyloid peptide has been observed upon interaction with sphingolipid-containing membranes. Structure similarity searches with the combinatorial extension method revealed the presence of a W-like domain in the human prion protein PrP and in the Alzheimer beta-amyloid peptide. In each case, synthetic peptides derived from the predicted W-like domain were found to interact with monomolecular films of galactosylceramide and sphingomyelin at the air-water interface. The W-like domain of PrP is a disulfide-linked loop (Cys(179)- Cys(214)) that includes the E200K mutation site associated with familial Creutzfeldt-Jakob disease. This mutation abrogated sphingomyelin recognition. The identification of a common sphingolipid-binding motif in gp120, PrP, and P-amyloid peptide underscores the role of lipid rafts in the pathogenesis of HIV-1, Alzheimer, and prion diseases and may provide new therapeutic strategies.