Protein C-Mannosylation and C-Mannosyl Tryptophan in Chemical Biology and Medicine

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.

Conservation, abundance, glycosylation profile, and localization of the TSP protein family in Cryptosporidium parvum

“…The first enrichment strategy made use of the 5G12 antibody, which was developed to recognize peptides bearing the C-mannosyl tryptophan protein modification ( 31 , 32 ). This unusual type of glycosylation, as well as O-linked glucosyl-β(1→3)-fucosylation [βGlc (1→3)αFuc], is commonly associated with TSR domains in metazoans ( 33 ) and apicomplexans like Plasmodium spp ( 34 , 35 ) and T. gondii ( 36 , 37 ). We suspected that these modifications existed in Cryptosporidium spp.…”

“…S2 ). It is likely that this glycan is localized to the classical CXX( S/T) S motif of the TSR domain, as it is in other apicomplexans ( 34 , 35 , 36 , 37 ) and metazoans ( 33 ). These data confirm that C-mannosylation occurs in C. parvum sporozoites and that it is only found on TSR proteins, at least in this stage of the life cycle.…”

Destabilization of vitelline membrane outer layer protein 1 homolog (VMO1) by C‐mannosylation

“…Over 30 C ‐mannosylated proteins have been reported since 1994, but the biological function of C ‐mannosylation is still covered in a veil. Since numerous substrate proteins belonging to the TSR1 superfamily were found, the functional analyses of C ‐mannosylation related to TSR1 domain were deeply studied [ 2 , 3 ]. Meanwhile, the role of C ‐mannosylation in proteins not containing TSR1 domain has not been elucidated yet.…”

“…C ‐mannosylation is a type of protein glycosylation that occurs at the indole‐C2 position of tryptophan in target proteins possessing the consensus motif in the endoplasmic reticulum (ER). Since C ‐mannosylation was first detected in RNase2 from human urine, approximately 30 C ‐mannosylation proteins have been reported [ 1 , 2 ]. These proteins are classified into two broad categories: TSR1 superfamily and type I cytokine receptors.…”

Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

“… 1104 C‐Mannosylation occurs on proteins in the ER and is regulated by four dpy‐19‐like C‐Man transferases (DPY19), 1105 which transfer monomeric α‐mannose to the substrate on the first Trp residue in the Trp‐X‐X‐Trp/Cys motif. 1106 C‐Mannosylation plays an important role in protein folding, sorting, and secretion, 1107 , 1108 and it has been determined that 18% of human proteins undergo C‐mannosylation during secretion and transmembrane transport. 1109 The known protein substrates of C‐mannosyltransferases include the TSR superfamily and type I cytokine receptor family.…”