O-mannosyl glycans: from yeast to novel associations with human disease

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Abstract

In yeasts and other fungi, O-mannosyl glycans constitute a major protein modification that is essential for cell viability. For several decades, protein O-mannosylation was considered a yeast-specific modification. Thus, it was especially interesting when it became evident that O-mannosyl glycans in mammals are not as rare as previously thought. O-mannosyl glycans are abundant in the mammalian brain and are also an abundant modification of α-dystroglycan, a component of the dystrophin–glycoprotein complex. Recently, mutations in genes that are or might be involved in the glycosylation of α-dystroglycan have been identified. Their association with neuromuscular diseases has focused the attention of different research areas on protein O-mannosylation.

Introduction

Glycoproteins are widespread in archaea, bacteria and eukarya 1., 2., 3.. In eukaryotic cells, glycosylation is the most common and complex protein modification known to date. The carbohydrate moieties not only modulate the physico-chemical properties of proteins but also fulfill specific functions in cells, such as mediating ligand–receptor interactions or quality control of secretory proteins 4., 5.. N- and O-linked glycosylation are the most common forms of protein glycosylation in eukaryotes [6]. N-glycans are linked to proteins via the amide group of an asparagyl residue, O-glycans via the hydroxy group of hydroxy amino acids. In all eukaryotic N-glycans, N-acetylglucosamine (GlcNAc) is found as the reducing terminal carbohydrate residue [6]. In contrast, O-linked glycans feature a variety of reducing terminal sugar residues [6], such as N-acetylgalactosamine (GalNAc), fucose (Fuc), glucose (Glc), GlcNAc, xylose (Xyl), galactose (Gal), arabinose (Ara) and O-linked mannose (Man), the focus of this review.

O-mannosyl glycans in eukaryotes were first identified in 1969 by Sentandreu and Northcote [7] in the bakers’ yeast Saccharomyces cerevisiae. Then, for many years, O-mannosyl glycans were considered a specific fungal protein modification. In the 1980s, Margolis and co-workers reported evidence of the presence of O-mannosyl glycans among oligosaccharides on chondroitin sulfate proteoglycans isolated from mammalian brain 8., 9.. The core structure suggested was Galβ1-4GlcNAcβ1-3Man-Ser/Thr, optionally containing fucose, sialic acid and/or sulfate. For more than ten years, these structures were considered rare glycans restricted to brain proteoglycans. However, not more than five years ago, it became obvious that O-mannosyl glycans in mammals are not as uncommon as previously thought 10., 11.. Very recently, they entered the stage of general interest because, in humans, defects in the synthesis of these carbohydrate chains have been linked to several forms of congenital muscular dystrophies (CMDs), which are often associated with brain abnormalities. Focusing on the protein O-mannosyltransferase (PMT) family of dolichyl phosphate-β-d-mannose:protein O-α-d-mannosyltransferases, we summarize what we have learned about protein O-mannosylation from the model organism yeast. We further review recent knowledge of protein O-mannosylation in higher eukaryotes and discuss its significance for CMDs.

Section snippets

Structures of O-mannosyl glycans

In all yeasts and fungi studied to date, the reducing terminal mannose residue of O-mannosyl glycans is α-linked to the hydroxy amino acids serine and threonine; further mannose residues can be added to form the α1,2-linked mannotriose Manα1-2Manα1-2Man-Ser/Thr [12]. Man1–3-Ser/Thr structures are processed according to yeast/fungi species. S. cerevisiae can add further mannose residues in α1,3 linkage to form short linear oligosaccharides that are up to five mannosyl residues long and can be

Biosynthesis of O-mannosyl glycans

The biosynthesis of O-mannosyl glycans has been studied most extensively in S. cerevisiae. It is initiated at the endoplasmic reticulum (ER) by an evolutionarily conserved family of PMTs [18]. The PMTs catalyze the transfer of a mannosyl residue from dolichyl-phosphate-activated mannose (Dol-P-β-d-Man), while inverting its anomeric configuration, to serine and threonine residues of proteins entering the secretory pathway [18]. An α-d-mannosyl linkage is formed. So far, determinants for the

The PMT family of protein O-mannosyltransferases

ScPmt1p was the first protein O-mannosyltransferase to be purified from S. cerevisiae (on the basis of its enzymatic activity) and the corresponding gene was cloned [31]. Due to the homology to ScPMT1, the PMT family has been identified [18]. It shows no marked similarity to any other family of glycosyltransferase. In S. cerevisiae, the PMT family is highly redundant (ScPmt1p–7p). In vivo protein O-mannosyltransferase activity has been demonstrated for Pmt1p–4p and Pmt6p [18]. Among the PMT

Functional roles of O-mannosyl glycans

In S. cerevisiae, protein O-mannosylation is essential for cell viability [45]. In particular, it is indispensable for cell wall integrity [18]. Impairment of O-mannosylation also affects the stability, localization and/or proper function of individual proteins 18., 40.. Furthermore, aberrant O-mannosylation can interfere with the retrograde transport of misfolded proteins across the membrane of the ER [46] and, recently, a possible regulatory role in initiation of N-glycosylation was suggested

O-mannosyl glycans in disease

In the past two years, several genes encoding known or putative glycosyltransferases have been identified and implicated in CMDs (Figure 3). Characteristic of this subclass of CMDs is a similar progression of the disease in all patients, namely varying degrees of muscular dystrophy (CMD), brain malformation (cobblestone lissencephaly) and abnormalities of the eye [49••]. This group of neuromuscular diseases includes neuronal migration disorders, which are associated with hypoglycosylation of

Conclusions

Summarizing the recent progress in the study of inheritable neuronal migration disorders, it is evident that, depending on the mutation, there is a wide overlapping clinical spectrum. Thus, for diagnosis, the clinical phenotype is not sufficient and it is necessary to confirm the mutation at the genetic level. Apparently, null mutations in POMT1, POMGnT1 and fukutin result in a WWS-like phenotype. As abnormal glycosylation of α-dystroglycan was observed in WWS, MEB and FCMD, they might share

Update

Recent work showed that the α-dystroglycan glycosylated epitope was not detected in muscle fibers and intramuscular peripheral nerves of a muscle biopsy from a patient affected by WWS carrying a homozygous frameshift mutation in POMT1 [64]. These data further support the suggestion that POMT1 is involved in the synthesis of O-mannosyl glycans in humans.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • of special interest

  • ••

    of outstanding interest

Acknowledgements

We thank all the present and former members in our labs who helped to throw light on yeast protein O-mannosylation and POMTs in mammals. We are especially thankful to Ten Feizi, who actually promoted a close collaboration between our labs.

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