SH2 Domains Serve as Lipid-Binding Modules for pTyr-Signaling Proteins.
SH2 Domains Serve as Lipid-Binding Modules for pTyr-Signaling Proteins.
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DOI：
10.1016/j.molcel.2016.01.027
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发表时间：
2016-04-07
期刊：
影响因子：
16
通讯作者：
Cho W
中科院分区：
文献类型：
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作者：
Park MJ;Sheng R;Silkov A;Jung DJ;Wang ZG;Xin Y;Kim H;Thiagarajan-Rosenkranz P;Song S;Yoon Y;Nam W;Kim I;Kim E;Lee DG;Chen Y;Singaram I;Wang L;Jang MH;Hwang CS;Honig B;Ryu S;Lorieau J;Kim YM;Cho W
Src-Homology 2(SH2)结构域是一个蛋白质相互作用结构域，指导着无数的磷酸酪氨酸(Py)信号通路。全基因组筛选显示，≈90%的SH2结构域与质膜脂结合，其中许多具有很高的肌醇磷脂特异性。它们使用与Py结合口袋分开的表面阳离子贴片结合脂类，从而独立结合脂类和Py基序。这些斑块形成用于识别特定脂头基团的凹槽或用于非特异性膜结合的平面，这两种类型的相互作用对于细胞功能和含有SH2结构域的蛋白质的调节都是重要的。用ZAP70进行的细胞学研究表明，多种脂类以时空特异性的方式结合其C端SH2结构域，从而在T细胞中对其蛋白结合和信号活动施加精细的时空控制。总之，这些研究揭示了脂类如何控制SH2结构域介导的细胞蛋白质-蛋白质相互作用网络，并提出了一种治疗调节Py信号通路的新策略。
The Src-homology 2 (SH2) domain is a protein interaction domain that directs myriad phosphotyrosine (pY) signaling pathways. Genome-wide screening of human SH2 domains reveals that ≈90% of SH2 domains bind plasma membrane lipids and many have high phosphoinositide specificity. They bind lipids using surface cationic patches separate from pY-binding pockets, thus binding lipids and the pY motif independently. The patches form grooves for specific lipid headgroup recognition or flat surfaces for non-specific membrane binding and both types of interaction is important for cellular function and regulation of SH2 domain-containing proteins. Cellular studies with ZAP70 showed that multiple lipids bind its C-terminal SH2 domain in a spatiotemporally specific manner and thereby exert exquisite spatiotemporal control over its protein binding and signaling activities in T cells. Collectively, these studies reveal how lipids control SH2 domain-mediated cellular protein-protein interaction networks and suggest a new strategy for therapeutic modulation of pY signaling pathways.