title: Lipids Regulate Lck Protein Activity through Their Interactions with the Lck Src Homology 2 Domain.
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.
authors.affiliation: From the Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607.
authors.forename: Ren
authors.initials: R
authors.lastname: Sheng
authors.affiliation: the Division of Integrative Biosciences and Biotechnology and.
authors.forename: Da-Jung
authors.initials: DJ
authors.lastname: Jung
authors.affiliation: the Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute, Columbia University, New York, New York 11032, and.
authors.forename: Antonina
authors.initials: A
authors.lastname: Silkov
authors.affiliation: From the Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607.
authors.forename: Hyunjin
authors.initials: H
authors.lastname: Kim
authors.affiliation: From the Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607.
authors.forename: Indira
authors.initials: I
authors.lastname: Singaram
authors.affiliation: From the Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607.
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Wang
authors.affiliation: From the Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607.
authors.forename: Yao
authors.initials: Y
authors.lastname: Xin
authors.affiliation: the Division of Integrative Biosciences and Biotechnology and.
authors.forename: Eui
authors.initials: E
authors.lastname: Kim
authors.affiliation: the Division of Integrative Biosciences and Biotechnology and.
authors.forename: Mi-Jeong
authors.initials: MJ
authors.lastname: Park
authors.affiliation: From the Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Thiagarajan-Rosenkranz
authors.affiliation: From the Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607.
authors.forename: Sean
authors.initials: S
authors.lastname: Smrt
authors.affiliation: the Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute, Columbia University, New York, New York 11032, and.
authors.forename: Barry
authors.initials: B
authors.lastname: Honig
authors.affiliation: the Department of Genetic Engineering, Kyung Hee University, Yongin 446-701, Korea.
authors.forename: Kwanghee
authors.initials: K
authors.lastname: Baek
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: From the Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607.
authors.forename: Justin
authors.initials: J
authors.lastname: Lorieau
authors.affiliation: 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.
authors.forename: You-Me
authors.initials: YM
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Wonhwa
authors.initials: W
authors.lastname: Cho
mesh_terms: D019943:Amino Acid Substitution; D006801:Humans; D019169:Jurkat Cells; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000235:genetics / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D018909:src Homology Domains
chemical_list: D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D011948:Receptors, Antigen, T-Cell; C060974:phosphatidylinositol 3,4,5-triphosphate; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
keywords: Lck; Src homology 2 domain (SH2 domain); T-cell receptor (TCR); cell signaling; phosphoinositide; plasma membrane