Abstract
C-Mannosylation is a post-translational modification of proteins in the endoplasmic reticulum. Monomeric α-mannose is attached to specific Trp residues at the first Trp in the Trp-x-x-Trp/Cys (W-x-x-W/C) motif of substrate proteins, by the action of C-mannosyltransferases, DPY19-related gene products. The acceptor substrate proteins are included in the thrombospondin type I repeat (TSR) superfamily, cytokine receptor type I family, and others. Previous studies demonstrated that C-mannosylation plays critical roles in the folding, sorting, and/or secretion of substrate proteins. A C-mannosylation-defective gene mutation was identified in humans as the disease-associated variant affecting a C-mannosylation motif of W-x-x-W of ADAMTSL1, which suggests the involvement of defects in protein C-mannosylation in human diseases such as developmental glaucoma, myopia, and/or retinal defects. On the other hand, monomeric C-mannosyl Trp (C-Man-Trp), a deduced degradation product of C-mannosylated proteins, occurs in cells and extracellular fluids. Several studies showed that the level of C-Man-Trp is upregulated in blood of patients with renal dysfunction, suggesting that the metabolism of C-Man-Trp may be involved in human kidney diseases. Together, protein C-mannosylation is considered to play important roles in the biosynthesis and functions of substrate proteins, and the altered regulation of protein C-manosylation may be involved in the pathophysiology of human diseases. In this review, we consider the biochemical and biomedical knowledge of protein C-mannosylation and C-Man-Trp, and introduce recent studies concerning their significance in biology and medicine.
Highlights
Site-directed mutagenesis studies of ribonuclease 2 (RNase 2) revealed that C-mannosylation was generated at the first Trp in the sequence W0 -x+1 -x+2 -W+3 within the protein, and the Trp residue at position +3 could be replaced by Phe
By using synthetic peptides with C-mannose, we showed that C-mannosylated tetrapeptide of C-Man-WSPW but not C-Man-Trp demonstrated an enhancing effect on the cytotoxicity of LPS by increasing the production of tumor necrosis factor-α (TNF-α), which suggested that the C-mannosylated TSR-derived W-x-x-W motif is involved in the regulation of LPS-related innate immunity [127]
The heat shock cognate protein 70 (Hsc70)-induced production and secretion of TNF-α were enhanced more by C-Man-WSPW than WSPW. These results indicated that the C-Man-WSPW peptide exerts a modulatory function in the Hsc70-related signaling pathway, the mechanical correlation between the enhanced LPS-induced signaling with the C-mannosylated peptide and Hsc70 was not clear
Summary
Monomeric C-Man-Trp was detected in human urine and blood [5], and the detailed structure was confirmed [6]. The structure of C-Man-Trp is unique in the sugar–amino acid linkage because of the C–C bond between mannose and. In the biosynthesis of the C-mannosyl Trp structure, a monomeric α-mannose is attached to the first Trp in the Trp-x-x-Trp/Cys (W-x-x-W/C) motif of substrate proteins by the action of C-mannosyltransferases in the endoplasmic reticulum (ER) [1,2,7]. Biosynthesis of C-mannosylated proteins is done by DPY19L1 and DPY19L3; biological functions of protein C-mannosylation and metabolism of monomeric CMan-Trp are not yet fully understood. This review describes the chemical and biochemical knowledge of protein C-mannosylation and C-Man-Trp and the recent progress of studies to reveal their significance in biomedical fields
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