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Mol Cell. 2016 Apr 7;62(1):7-20. doi: 10.1016/j.molcel.2016.01.027. Epub 2016 Mar 24.

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

Author information

1
Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, Korea.
2
Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA.
3
Department of Biochemistry and Molecular Biophysics and Howard Hughes Medical Institute, Columbia University, New York, NY 11032, USA.
4
Academy of Immunology and Microbiology, Institute for Basic Science, Pohang 790-784, Korea.
5
Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Korea.
6
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.
7
Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA. Electronic address: wcho@uic.edu.

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.

PMID:
27052731
PMCID:
PMC4826312
DOI:
10.1016/j.molcel.2016.01.027
[Indexed for MEDLINE]
Free PMC Article

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