McRobert E Anne, Tikoo Anjali, Gallicchio Marisa A, Cooper Mark E, Bach Leon A
Present address and address for correspondence: E. Anne McRobert, Central and Eastern Clinical School, Department of Medicine, Monash University, AMREP, Alfred Hospital, Prahran, Vic 3181, Australia.
Ann N Y Acad Sci. 2005 Jun;1043:617-24. doi: 10.1196/annals.1333.070.
ERM proteins (ezrin, radixin, and moesin) have recently been identified as a new class of AGE-binding proteins. ERM proteins link the plasma membrane with the actin cytoskeleton and regulate cell shape, motility, adhesion, and signal transduction. ERM proteins have three structural domains: the N-terminal domain, a coiled midregion, and the C-terminal domain. The N-terminal domain binds to a number of plasma membrane ligands and is involved in signal transduction, while the C-domain binds to actin filaments. Binding studies with isolated structural domains showed that glycated proteins bind to an epitope within the N-terminal domain of ezrin (aa 1-324). It is postulated that some of the cellular effects of AGEs leading to diabetic complications may be mediated by binding to this region of ezrin, thereby interrupting the cross-linking between the plasma membrane and actin cytoskeleton and downstream signaling pathways. Indeed, changes in actin arrangement, cell shape, and adhesion have been described in diabetes, and AGE-BSA inhibits ezrin-dependent tubulogenesis of LLC-PK1 proximal tubular cells. For future development of antagonists, further identification of the ezrin-binding epitope for glycated proteins is required.
ERM蛋白（埃兹蛋白、根蛋白和膜突蛋白）最近被鉴定为一类新的晚期糖基化终末产物（AGE）结合蛋白。ERM蛋白将质膜与肌动蛋白细胞骨架相连，并调节细胞形状、运动性、黏附及信号转导。ERM蛋白有三个结构域：N端结构域、卷曲的中间区域和C端结构域。N端结构域与多种质膜配体结合并参与信号转导，而C结构域与肌动蛋白丝结合。对分离结构域的结合研究表明，糖化蛋白与埃兹蛋白N端结构域内的一个表位（氨基酸1 - 324）结合。据推测，AGEs导致糖尿病并发症的一些细胞效应可能是通过与埃兹蛋白的这一区域结合介导的，从而中断质膜与肌动蛋白细胞骨架之间的交联及下游信号通路。事实上，糖尿病中已描述了肌动蛋白排列、细胞形状和黏附的变化，且AGE - 牛血清白蛋白抑制LLC - PK1近端肾小管细胞的埃兹蛋白依赖性小管形成。为了拮抗剂的未来开发，需要进一步鉴定糖化蛋白的埃兹蛋白结合表位。
