Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 291, Issue 34, Pages 17639-17650Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M116.720284
Keywords
cell signaling; phosphoinositide; plasma membrane; Src homology 2 domain (SH2 domain); T-cell receptor (TCR); Lck
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Funding
- National Institutes of Health [GM68849, GM110128, GM030518, GM094597, CA121852]
- National Research Foundation of Korea [NRF-2013R1A1A2074573]
- World Class University Program by the Korean Government [R31-2008-000-10105-0]
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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 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.
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