Molecular basis of C‐mannosylation – a structural perspective

Abstract

The structural and functional diversity of proteins can be enhanced by numerous post-translational modifications. C-mannosylation is a rare form of glycosylation consisting of a single alpha or beta Dmannopyranose forming a carbon-carbon bond with the pyrrole ring of a tryptophan residue. Despite first being discovered in 1994, C-mannosylation is still poorly understood and 3D structures are available for only a fraction of the total predicted C-mannosylated proteins. Here we present the first comprehensive review of C-mannosylated protein structures by analysing the data for all ten proteins with C-mannosylation/s deposited in the Research Collaboratory for Structural Bioinformatics Protein Data Bank. We analysed in detail the WXXW/WXXWXXW consensus motif and the highly conserved pair of arginine residues in thrombospondin type-1 repeat Cmannosylation sites or homologous arginine residues in other domains. Furthermore, we identified a conserved PXP sequence C-terminal of the C-mannosylation site. The PXP motif forms a tight turn region in the polypeptide chain and its universal conservation in C-mannosylated protein is worthy of further experimental study. The stabilisation of C-mannopyranosyl groups was demonstrated through hydrogen bonding with arginine and other charged or polar amino acids. Where possible, the structural findings were linked to other functional studies demonstrating the role of Cmannosylation in protein stability, secretion, or function. With the current technological advances in structural biology, we hope to see more progress in the study of C-mannosylation that may correspond to discoveries of novel C-mannosylation pathways and functions with implications for human health and biotechnology.

Elucidating the Interactome of G Protein-Coupled Receptors and Receptor Activity-Modifying Proteins

“…A recent paper reports that RAMP1 contains a consensus motif WXXW for C-mannosylation ( Mizuta et al, 2022 ). C-mannosylation is a rare PTM consisting of a carbon-carbon bond linking a single α - or β -D-mannopyranose to the pyrrole ring of the first tryptophan residue in the WXXW motif ( Crine and Acharya, 2021 ). The C-mannosylation of RAMP1 at tryptophan 56 enhances protein stability.…”

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

“…C‐Mannosylation is a relatively rare form of protein glycosylation. The monomeric D‐mannopyranose bound with the C‐2 position of the pyrrole ring of the tryptophan residue to form a carboncarbon bond 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 .…”

Glycomimetics for the inhibition and modulation of lectins

“…The diagnostic potential of glycomimetics is exemplified by [ 18 F]fluorodeoxyglucose (5) frequently used as probe in positron emission tomography (PET). 60 In some glycomimetics, systemic distribution is not required, such as in acarbose 61 (6) and zanamivir 62 (7) due to a desired local effect. In others, a sufficient therapeutic effect is achieved after parenteral administration due to improved metabolic stability, for which the heparin glycomimetic fondaparinux (8) serves as example.…”

“…On the other hand, phosphate-linked glycans or C-mannosides belong to the rare glycosylation types. 5,6 As a further form of glycosylation glycosylphosphatidylinositol (GPI) anchors are used for extracellular presentation of proteins. 7,8 A GPI anchor consists of an inositol phospholipid linked to a glucosamine, followed by a trisaccharide and an ethanolamine phosphate, to which the C-terminus of the protein is bound via an amide bond.…”