Molecular dynamics of the recruitment of immunoreceptor signaling module DAP12 homodimer to lipid raft boundary regulated by PIP2
Abstract
Lipid raft microdomain of the plasma membrane is implicated in various biological and pathological processes. The involvement of lipid raft in T cell receptor (TCR) signal transduction has been widely studied, whereas the role of these structures in immunoreceptor signaling by DAP12 in natural killing (NK) cells remains largely unknown. Here, we demonstrate that phosphatidylinositol 4,5-bisphosphate (PIP2) lipid localized to lipid raft boundary in our coarse-grained (CG) model raft-forming membrane, and this negatively charged lipid recruits DAP12 homodimer into lipid raft boundary through protein–lipid interaction between the basic-rich regions and signaling immunoreceptor tyrosine-based activation motifs (ITAMs) of DAP12 and PIP2. Furthermore, our results reveal that the protein–lipid interaction can be disrupted by Ca 2+, which competitively binds to PIP2 instead of DAP12. As a result, the cytoplasmic region of DAP12 homodimer is dissociated from the membrane back to the nonraft domain, and the ITAMs are exposed to allow further downstream signaling. These findings provide fundamental insights to understand the mechanism of signal transduction in NK cells regulated by membrane microenvironment.
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Adipocytes promote macrophage recruitment, then adipocytes and immune cells secrete more adipokines such as leptin, chemerin, resistin, and more cytokines such as TNF-α, ILs, INF-γ, creating a circumstance of low-grade inflammation.
“Specifically, adipocytes promote macrophage recruitment (21), then adipocytes and immune cells secrete more adipokines such as leptin, chemerin, resistin, and more cytokines such as tumor necrosis factor-α (TNF-α), interleukins (ILs), interferon-γ (INF-γ) (22–25), creating a circumstance of low-grade inflammation.”
From Diabetes and Sarcopenic Obesity: Pathogenesis, Diagnosis, and Treatments (2020) · cites this paper as [24]
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Self-citation
- Authors
- Dong, R., Tan, Y., Fan, A., Liao, Z., Liu, H., & Wei, P.
- Affiliations
- Beijing University of Chinese Medicine (CN)
- Nanyang Technological University (SG)
- Beijing University of Chemical Technology (CN)
- Corresponding author
- Wei, Peng
- Venue
- The Journal of Physical Chemistry B
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-12-30
- Volume
- 124
- Issue
- 3
- Pages
- 504-510
- ISSN
- 1520-5207 (ISSN-L)
- 1520-6106
- OpenAlex
- W2998337275
- Cited by
- 22
- References
- 36
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 4 · 2023: 3 · 2022: 3 · 2021: 4 · 2020: 4
- FWCI
- 0.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- The Journal of Physical Chemistry B (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education of the People's Republic of China (2017-JYB-JS-009, 2018-JYBZZ-JS-011)
- National Natural Science Foundation of China (31800652)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- lipid rafts, phosphatidylinositol 4,5-bisphosphate, protein-lipid interactions, immunoreceptor signaling, natural killer cells, ITAM, calcium binding, membrane microenvironment, T cell receptor signaling, coarse-grained membrane model, signal transduction
- MeSH terms
- Cholesterol, Humans, Membrane Proteins, Phosphatidylcholines, Phosphatidylinositols, Protein Binding, 1,2-Dipalmitoylphosphatidylcholine, Membrane Microdomains, Adaptor Proteins, Signal Transducing, Molecular Dynamics Simulation
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