Mi-Jeong Park,1,6 Ren Sheng,2,6 Antonina Silkov,3,6 Da-Jung Jung,1,6 Zhi-Gang Wang,2 Yao Xin,2 Hyunjin Kim,2 Pallavi Thiagarajan-Rosenkranz,2 Seohyeon Song,1 Youngdae Yoon,2,7 Wonhee Nam,1 Ilshin Kim,4 Eui Kim,1 Dong-Gyu Lee,1 Yong Chen,2 Indira Singaram,2 Li Wang,2 Myoung Ho Jang,4 Cheol-Sang Hwang,5 Barry Honig,3 Sungho Ryu,5 Justin Lorieau,2 You-Me Kim,1,5,* and Wonhwa Cho2,*
1Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, Korea
2Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA
3Department of Biochemistry and Molecular Biophysics and Howard Hughes Medical Institute, Columbia University, New York, NY 11032, USA
4Academy of Immunology and Microbiology, Institute for Basic Science, Pohang 790-784, Korea
5Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Korea
6Co-first author
7Present address: Department of Environmental Health Science, Konkuk University, Seoul 05029, Korea
*Correspondence: You-Me Kim, Wonhwa Cho
Summary
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.