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J Biol Chem. 2016 Aug 19;291(34):17639-50. doi: 10.1074/jbc.M116.720284. Epub 2016 Jun 22.

Lipids Regulate Lck Protein Activity through Their Interactions with the Lck Src Homology 2 Domain.

Author information

1
From the Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607.
2
the Division of Integrative Biosciences and Biotechnology and.
3
the Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute, Columbia University, New York, New York 11032, and.
4
the Department of Genetic Engineering, Kyung Hee University, Yongin 446-701, Korea.
5
Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Korea.
6
the Division of Integrative Biosciences and Biotechnology and Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Korea, youmekim@postech.ac.kr.
7
From the Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607, the Department of Genetic Engineering, Kyung Hee University, Yongin 446-701, Korea wcho@uic.edu.

Abstract

Lymphocyte-specific protein-tyrosine kinase (Lck) plays an essential role in T cell receptor (TCR) signaling and T cell development, but its activation mechanism is not fully understood. To explore the possibility that plasma membrane (PM) lipids control TCR signaling activities of Lck, we measured the membrane binding properties of its regulatory Src homology 2 (SH2) and Src homology 3 domains. The Lck SH2 domain binds anionic PM lipids with high affinity but with low specificity. Electrostatic potential calculation, NMR analysis, and mutational studies identified the lipid-binding site of the Lck SH2 domain that includes surface-exposed basic, aromatic, and hydrophobic residues but not the phospho-Tyr binding pocket. Mutation of lipid binding residues greatly reduced the interaction of Lck with the ζ chain in the activated TCR signaling complex and its overall TCR signaling activities. These results suggest that PM lipids, including phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate, modulate interaction of Lck with its binding partners in the TCR signaling complex and its TCR signaling activities in a spatiotemporally specific manner via its SH2 domain.

KEYWORDS:

Lck; Src homology 2 domain (SH2 domain); T-cell receptor (TCR); cell signaling; phosphoinositide; plasma membrane

PMID:
27334919
PMCID:
PMC5016160
DOI:
10.1074/jbc.M116.720284
[Indexed for MEDLINE]
Free PMC Article

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