Lipids Regulate Lck Protein Activity through Their Interactions with the Lck Src Homology 2 Domain
Open accessAbstract
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.
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Certain PZD-domain containing proteins such as Dvl2 can be directly activated by cholesterol within the inner leaflet of the plasma membrane.
“Recent reports suggest that certain PZD-domain containing proteins such as Dvl2 can be directly activated by cholesterol within the inner leaflet of the plasma membrane (43, 44, 82–84).”
From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [82]
The Abstract (page unavailable) reports that PDZ domains bind plasma-membrane lipids and that this binding is important for their host proteins’ function. The References list studies of cholesterol interactions with PDZ proteins and cholesterol-dependent Wnt signaling, but this paper does not state that cholesterol directly activates Dvl2 or locate that interaction in the inner leaflet. (LLM, conf=0.78)
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An inducible translocation strategy to rapidly activate and inhibit small GTPase signaling pathways.
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A model binding site for testing scoring functions in molecular docking.
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Sheng, R., Chen, Y., Yung Gee, H., Stec, E., Melowic, H. R., Blatner, N. R., Tun, M. P., Kim, Y., Källberg, M., Fujiwara, T. K., et al. (2012) · Nature Communications · doi:10.1038/ncomms2221 · Cited by 179 · see citing works
Self-citationCholesterol selectively activates canonical Wnt signalling over non-canonical Wnt signalling
Sheng, R., Kim, H., Lee, H., Xin, Y., Chen, Y., Tian, W., Cui, Y., Choi, J.-C., Doh, J., Han, J.-K., et al. (2014) · Nature Communications · doi:10.1038/ncomms5393 · Cited by 157 · see citing works
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Research works printed but not linked: 2
- Hardwick, J. S., and Sefton, B. M. (1995) Activation of the Lck tyrosine protein kinase by hydrogen peroxide requires the phosphorylation of Tyr- 394. Proc. Natl. Acad. Sci. U.S.A. 92, 4527-4531
- Stephen, T. L., Wilson, B. S., and Laufer, T. M. (2012) Subcellular distri- bution of Lck during CD4 T-cell maturation in the thymic medulla regu- lates the T-cell activation threshold. Proc. Natl. Acad. Sci. U.S.A. 109, 7415-7420
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Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells
Bendre, S. V., Wang, Y., Hajyousif, B., K C, R., Bhogale, S. G., Pradeep, D., Krawczynska, N., Schane, C. P., Weisser, E., Singh, A., et al. (2026) · Science Advances · doi:10.1126/sciadv.adx5490 · Cited by 8 · see citing works
“…PDZ domain containing proteins such as Dvl2 can be directly activated by cholesterol within the inner leaflet of the plasma membrane ( 50 – 52 , 94 – 96 In summary, we demonstrate that the activity of the cholesterol efflux and translocation protein, ABCA1, has critical implications in the…”
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- Authors
- Sheng, R., Jung, D.-J., Silkov, A., Kim, H., Singaram, I., Wang, Z.-G., Xin, Y., Kim, E., Park, M.-J., Thiagarajan-Rosenkranz, P., Smrt, S., Honig, B., Baek, K., Ryu, S., Lorieau, J., Kim, Y.-M., & Cho, W.
- Affiliations
- University of Illinois Chicago (US)
- Howard Hughes Medical Institute (US)
- Kyung Hee University (KR)
- Pohang University of Science and Technology (KR)
- Corresponding author
- Kim, You-Me
- Cho, Wonhwa
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2016-08
- Volume
- 291
- Issue
- 34
- Pages
- 17639-17650
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC5016160
- OpenAlex
- W2507273126
- Cited by
- 43
- References
- 4
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 2 · 2023: 8 · 2022: 6 · 2021: 4 · 2020: 6 · 2019: 2 · 2018: 6 · 2017: 4 · 2016: 1
- FWCI
- 2.25
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Open Access System for Information Sharing (Pohang University of Science and Technology) (submittedVersion)
- Funders
- National Institutes of Health (GM68849, GM110128, GM030518, GM094597, CA121852)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- Lck, lipid binding, SH2 domain, SH3 domain, plasma membrane lipids, T cell receptor signaling, phosphatidylinositol 4,5-bisphosphate, phosphatidylinositol 3,4,5-trisphosphate, lipid binding sites, T cell development
- MeSH terms
- Humans, Receptors, Antigen, T-Cell, Signal Transduction, Phosphatidylinositol Phosphates, src Homology Domains, Jurkat Cells, Phosphatidylinositol 4,5-Diphosphate, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), Amino Acid Substitution, Mutation, Missense
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