期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 291, 期 17, 页码 9310-9321出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M116.722066
关键词
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资金
- Wellcome Trust
- Biotechnology and Biological Sciences Research Council [BB/H019383/1, BB/H024697/1, BB/I013865/1] Funding Source: researchfish
- The Francis Crick Institute [10093] Funding Source: researchfish
- Wellcome Trust [106292/Z/14/Z] Funding Source: researchfish
- BBSRC [BB/H024697/1, BB/H019383/1, BB/I013865/1] Funding Source: UKRI
Dendritic epidermal T cells (DETC) form a skin-resident gamma delta T cell population that makes key contributions to cutaneous immune stress surveillance, including non-redundant contributions to protection from cutaneous carcinogens. How DETC become uniquely associated with the epidermis was in large part solved by the identification of Skint-1, the prototypic member of a novel B7-related multigene family. Expressed only by thymic epithelial cells and epidermal keratinocytes, Skint-1 drives specifically the development of DETC progenitors, making it the first clear candidate for a selecting ligand for non-MHC/CD1-restricted T cells. However, the molecular mechanisms underpinning Skint-1 activity are unresolved. Here, we provide evidence that DETC selection requires Skint-1 expression on the surface of thymic epithelial cells, and depends upon specific residues on the CDR3-like loop within the membrane-distal variable domain of Skint-1 (Skint-1 DV). Nuclear magnetic resonance of Skint-1 DV revealed a core tertiary structure conserved across the Skint family, but a highly distinct surface charge distribution, possibly explaining its unique function. Crucially, the CDR3-like loop formed an electrostatically distinct surface, featuring key charged and hydrophobic solvent-exposed residues, at the membrane-distal tip of DV. These results provide the first structural insights into the Skint family, identifying a putative receptor binding surface that directly implicates Skint-1 in receptor-ligand interactions crucial for DETC selection.
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