Journal
OPEN BIOLOGY
Volume 11, Issue 9, Pages -Publisher
ROYAL SOC
DOI: 10.1098/rsob.210104
Keywords
dystroglycan; post-translational glycosylation; M3 core structure; laminin-binding glycoepitope; glycosyltransferases; protein evolution
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Funding
- British Heart Foundation [CH/1/32804]
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The DG complex plays a key role in muscle stability in Metazoa, with mutations in enzymes involved in glycosylation of alpha-DG leading to severe neuromuscular disorders. Investigating the evolution of these modifying enzymes reveals the importance of glycosylation in modulating the connection between sarcolemma and basement membranes, ultimately supporting skeletal muscle stability and movement.
The dystroglycan (DG) complex plays a pivotal role for the stabilization of muscles in Metazoa. It is formed by two subunits, extracellular alpha-DG and transmembrane beta-DG, originating from a unique precursor via a complex post-translational maturation process. The alpha-DG subunit is extensively glycosylated in sequential steps by several specific enzymes and employs such glycan scaffold to tightly bind basement membrane molecules. Mutations of several of these enzymes cause an alteration of the carbohydrate structure of alpha-DG, resulting in severe neuromuscular disorders collectively named dystroglycanopathies. Given the fundamental role played by DG in muscle stability, it is biochemically and clinically relevant to investigate these post-translational modifying enzymes from an evolutionary perspective. A first phylogenetic history of the thirteen enzymes involved in the fabrication of the so-called 'M3 core' laminin-binding epitope has been traced by an overall sequence comparison approach, and interesting details on the primordial enzyme set have emerged, as well as substantial conservation in Metazoa. The optimization along with the evolution of a well-conserved enzymatic set responsible for the glycosylation of alpha-DG indicate the importance of the glycosylation shell in modulating the connection between sarcolemma and surrounding basement membranes to increase skeletal muscle stability, and eventually support movement and locomotion.
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