Structural Research of Membrane-Spanning 4-Domain (MS4) Family
Members of the transmembrane 4 domain (MS4) family are selectively expressed in immunoreceptive cells and macrophages and bind to different classes of immune receptors and regulate their signaling activity. Members of the MS4A family can serve as candidate biomarkers and therapeutic targets for a variety of diseases.
Research Progress on Structure of MS4A Protein Family
Three members of this family, MS4A1 (CD20), MS4A2 (FC-εriβ) and MS4A3 (HTm4), have been cloned and show sequence identity. The N-terminal and C-terminal of CD20 are located in the cytoplasm. The CD20 structure has four transmembrane helices (TM) and two extracellular loops ECL1 and ECL2. The second of the two outer rings is longer and contains disulfide bonds. FC-εRIβ is highly homologous to CD20. FC-εRIβ is part of a tetramer receptor complex consisting of one alpha chain, one beta chain, and two gamma chains.
Mechanism of Action of Members of the MS4A Protein Family
The MS4A protein family plays a role in the pathogenesis of disease. When expressed in fibroblasts, CD20 acts as a Ca2+ channel to control ion transport. The expression of CD20 is limited to B cell precursors and mature B cells. The IGE-FC-ε RIβ receptor aggregation complex is reconstructed into the lipid bilayer to generate Ca2+ channel activity, and IGE receptors have recently been reported to activate the Ca2+ conductance of FC-εRIβ in mast cells. HTm4 is present in lymphocytes and bone marrow hematopoietic cells. The function of HTm4 is not clear, and it may be related to cell proliferation. During t-cell development, MS4a4B expression is tightly regulated, and MS4a4B expression promotes Th1 function and/or differentiation.
Figure 1. Cryo-EM reconstruction of the CD20: RTX Fab complex at a resolution of 3.3 Å. (Lionel Rougé, et al,
2020)
| Protein | Organism | Method | Resolution | PDB Entry ID |
| GA101 provides insights into the molecular basis for the type I/type II distinction of anti-CD20 antibodies | Homo sapiens | X-ray diffraction | 1.60 Å | 3PP4 |
| CD20 in complex with rituximab Fab | Homo sapiens | Cryo-EM single particle analysis | 3.30 Å | 6VGA |
| Full-length CD20 in complex with Rituximab Fab | Homo sapiens | Cryo-EM single particle analysis | 3.69 Å | 6Y90 |
| Full-length CD20 in complex with Ofatumumab Fab | Homo sapiens | Cryo-EM single particle analysis | 4.73 Å | 6Y92 |
| Full-length CD20 in complex with Obinutuzumab Fab | Homo sapiens | Cryo-EM single particle analysis | 4.33 Å | 6Y97 |
| Full-length CD20 in complex with Obinutuzumab Fab | Homo sapiens | Cryo-EM single particle analysis | 4.20 Å | 6Y9A |
| Chimeric Antibody C2H7 Fab in complex with a CD20 Peptide | Homo sapiens | X-ray diffraction | 2.61 Å | 3BKY |
| Rituximab Fab in complex with an epitope peptide | Homo sapiens | X-ray diffraction | 2.60 Å | 2OSL |
Table 1. Structural research of membrane-spanning 4-domain (MS4) family.
We usually use X-ray crystallography and cryo-electron microscopy (cryo-EM) to analyze the structure of MS4 family proteins. The mechanism of action in the pathogenesis of disease and the development of related drugs were further discussed through structural analysis.
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References
- Zheng Z, et al. Role of the membrane spanning 4A (MS4A) gene family in lung adenocarcinoma. Research Square; 2022.
- Xu H, et al. Patterns of expression, membrane localization, and effects of ectopic expression suggest a function for MS4a4B, a CD20 homolog in Th1 T cells. Blood. 2006, 107(6):2400-2408.
- Lionel Rougé, et al. Structure of CD20 in complex with the therapeutic monoclonal antibody rituximab. Science, 2020, 367:1224-1230.
