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

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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.
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Issue Date
2016-08
Language
English
Article Type
Article
Keywords

T-CELL-ACTIVATION; MEMBRANE-BINDING; FAMILY KINASES; SIGNALING PATHWAYS; LIVING CELLS; SH2 DOMAINS; C2 DOMAINS; DOCKING; SURFACE; SYSTEM

Citation

JOURNAL OF BIOLOGICAL CHEMISTRY, v.291, no.34, pp.17639 - 17650

ISSN
0021-9258
DOI
10.1074/jbc.M116.720284
URI
http://hdl.handle.net/10203/240759
Appears in Collection
MSE-Journal Papers(저널논문)
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