SH2 Domains Serve as Lipid-Binding Modules for pTyr-Signaling Proteins.

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 are 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, this study reveals how lipids control SH2 domain-mediated cellular protein-protein interaction networks and suggest a new strategy for therapeutic modulation of pY-signaling pathways. Copyright © 2016 Elsevier Inc. All rights reserved.

Citation

Mi-Jeong Park, Ren Sheng, Antonina Silkov, Da-Jung Jung, Zhi-Gang Wang, Yao Xin, Hyunjin Kim, Pallavi Thiagarajan-Rosenkranz, Seohyeon Song, Youngdae Yoon, Wonhee Nam, Ilshin Kim, Eui Kim, Dong-Gyu Lee, Yong Chen, Indira Singaram, Li Wang, Myoung Ho Jang, Cheol-Sang Hwang, Barry Honig, Sungho Ryu, Justin Lorieau, You-Me Kim, Wonhwa Cho. SH2 Domains Serve as Lipid-Binding Modules for pTyr-Signaling Proteins. Molecular cell. 2016 Apr 7;62(1):7-20

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PMID: 27052731

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