Abstract
The human C-type lectin 18 (clec18) gene cluster, which contains three clec18a, clec18b, and clec18c loci, is located in human chromosome 16q22. Although the amino acid sequences of CLEC18A, CLEC18B, and CLEC18C are almost identical, several amino acid residues located in the C-type lectin-like domain (CTLD) and the sperm-coating protein/Tpx-1/Ag5/PR-1/Sc7 (SCP/TAPS) domain, also known as the cysteine-rich secretory proteins/antigen 5/pathogenesis-related 1 proteins (CAP) domain, are distinct from each other. Genotyping by real-time PCR and sequencing further shows the presence of multiple alleles in clec18a/b/c loci. Flow cytometry analysis demonstrates that CLEC18 (CLEC18A, -B, and -C) are expressed abundantly in human peripheral blood cells. Moreover, CLEC18 expression is further up-regulated when monocytes differentiate into macrophages and dendritic cells. Immunofluorescence staining reveals that CLEC18 are localized in the endoplasmic reticulum, Golgi apparatus, and endosome. Interestingly, CLEC18 are also detectable in human sera and culture supernatants from primary cells and 293T cells overexpressing CLEC18. Moreover, CLEC18 bind polysaccharide in Ca(2+)-independent manner, and amino acid residues Ser/Arg(339) and Asp/Asn(421) in CTLD domain contribute to their differential binding abilities to polysaccharides isolated from Ganoderma lucidum (GLPS-F3). The Ser(339) (CLEC18A) → Arg(339) (CLEC18A-1) mutation completely abolishes CLEC18A-1 binding to GLPS-F3, and a sugar competition assay shows that CLEC18 preferentially binds to fucoidan, β-glucans, and galactans. Because proteins with the SCP/TAPS/CAP domain are able to bind sterol and acidic glycolipid, and are involved in sterol transport and β-amyloid aggregation, it would be interesting to investigate whether CLEC18 modulates host immunity via binding to glycolipids, and are also involved in glycolipid transportation and protein aggregation in the future.
Highlights
CLEC18 is a novel C-type lectin not being characterized
Compared with CLEC18A, CLEC18C is almost identical with CLEC18A except 2 amino acids (Thr91 3 Ile91, Val118 3 Als118) located in SCP/TAPS/cysteine-rich secretory proteins/antigen 5/pathogenesis-related proteins (CAP) domain and 1 amino acid (Asp421 3 Asn421) in WND motif located in C-type lectin-like domain (CTLD)
1) It is surprising to find that CLEC18A/C bind GLPS-F3 in a Ca2ϩ-independent manner, even though the typical WND domain was present in CLEC18A. 2) Presence of the Gln399Pro400-Asp401 tripeptide motif in CLEC18 CTLD predicts binding specificity to galactose and GalNAc
Summary
Results: The amino acid residue in the C-type lectin-like domain of CLEC18 contribute to the differential glycan-binding ability. 2) Translation of clec cDNA predicted an N-linked polypeptide with a C-type lectin domain (CTLD) in the C terminus, and the SCP/TAPS (sperm-coating protein Tpx-1/Ag5/PR-1/Sc7) domain ( known as CAP (cysteine-rich secretory proteins, antigen 5, and pathogenesis-related 1) domain), which is a conserved tertiary ␣--␣ structure stabilized by disulfide bonds. Amino acid residues Ser/ Arg339 and Asp/Asn421 located in the CTLD domain contribute to their differential glycan binding specificity. This observation suggests that CLEC18 may bind to various glycoconjugates with distinct affinity, and contribute to differential immune responses to glycoconjugates expressed on foreign antigens or altered self-antigen in ER, Golgi apparatus, and endosomes
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