title: SH2 Domains Serve as Lipid-Binding Modules for pTyr-Signaling Proteins.
abstract: 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.
authors.affiliation: Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, Korea.
authors.forename: Mi-Jeong
authors.initials: MJ
authors.lastname: Park
authors.affiliation: Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Ren
authors.initials: R
authors.lastname: Sheng
authors.affiliation: Department of Biochemistry and Molecular Biophysics and Howard Hughes Medical Institute, Columbia University, New York, NY 11032, USA.
authors.forename: Antonina
authors.initials: A
authors.lastname: Silkov
authors.affiliation: Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, Korea.
authors.forename: Da-Jung
authors.initials: DJ
authors.lastname: Jung
authors.affiliation: Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Wang
authors.affiliation: Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Yao
authors.initials: Y
authors.lastname: Xin
authors.affiliation: Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Hyunjin
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Thiagarajan-Rosenkranz
authors.affiliation: Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, Korea.
authors.forename: Seohyeon
authors.initials: S
authors.lastname: Song
authors.affiliation: Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Youngdae
authors.initials: Y
authors.lastname: Yoon
authors.affiliation: Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, Korea.
authors.forename: Wonhee
authors.initials: W
authors.lastname: Nam
authors.affiliation: Academy of Immunology and Microbiology, Institute for Basic Science, Pohang 790-784, Korea.
authors.forename: Ilshin
authors.initials: I
authors.lastname: Kim
authors.affiliation: Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, Korea.
authors.forename: Eui
authors.initials: E
authors.lastname: Kim
authors.affiliation: Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, Korea.
authors.forename: Dong-Gyu
authors.initials: DG
authors.lastname: Lee
authors.affiliation: Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Indira
authors.initials: I
authors.lastname: Singaram
authors.affiliation: Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Academy of Immunology and Microbiology, Institute for Basic Science, Pohang 790-784, Korea.
authors.forename: Myoung Ho
authors.initials: MH
authors.lastname: Jang
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Korea.
authors.forename: Cheol-Sang
authors.initials: CS
authors.lastname: Hwang
authors.affiliation: Department of Biochemistry and Molecular Biophysics and Howard Hughes Medical Institute, Columbia University, New York, NY 11032, USA.
authors.forename: Barry
authors.initials: B
authors.lastname: Honig
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Korea.
authors.forename: Sungho
authors.initials: S
authors.lastname: Ryu
authors.affiliation: Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Lorieau
authors.affiliation: Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, Korea; Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Korea. Electronic address: youmekim@postech.ac.kr.
authors.forename: You-Me
authors.initials: YM
authors.lastname: Kim
authors.affiliation: Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA. Electronic address: wcho@uic.edu.
authors.forename: Wonhwa
authors.initials: W
authors.lastname: Cho
mesh_terms: D001665:Binding Sites; D002478:Cells, Cultured; D006801:Humans; D019169:Jurkat Cells; D050356:Lipid Metabolism; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D019000:Phosphotyrosine / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000737:chemistry* / Q000378:metabolism*; D018909:src Homology Domains
chemical_list: D019000:Phosphotyrosine; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human