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- Title
Functional implications of MIR domains in protein O-mannosylation.
- Authors
Chiapparino, Antonella; Grbavac, Antonija; Jonker, Hendrik R. A.; Hackmann, Yvonne; Mortensen, Sofia; Zatorska, Ewa; Schott, Andrea; Stier, Gunter; Saxena, Krishna; Wild, Klemens; Schwalbe, Harald; Strahl, Sabine; Sinning, Irmgard
- Abstract
Protein O-mannosyltransferases (PMTs) represent a conserved family of multispanning endoplasmic reticulum membrane proteins involved in glycosylation of S/T-rich protein substrates and unfolded proteins. PMTs work as dimers and contain a luminal MIR domain with a β-trefoil fold, which is susceptive for missense mutations causing a-dystroglycanopathies in humans. Here, we analyze PMT-MIR domains by an integrated structural biology approach using X-ray crystallography and NMR spectroscopy and evaluate their role in PMT function in vivo. We determine Pmt2- and Pmt3-MIR domain structures and identify two conserved mannose-binding sites, which are consistent with general b-trefoil carbohydrate-binding sites (α, β), and also a unique PMT2-subfamily exposed FKR motif. We show that conserved residues in site a influence enzyme processivity of the Pmt1-Pmt2 heterodimer in vivo. Integration of the data into the context of a Pmt1-Pmt2 structure and comparison with homologous β-trefoil -- carbohydrate complexes allows for a functional description of MIR domains in protein O-mannosylation.
- Subjects
PROTEIN domains; MEMBRANE proteins; X-ray crystallography; NUCLEAR magnetic resonance spectroscopy; MISSENSE mutation
- Publication
eLife, 2020, p1
- ISSN
2050-084X
- Publication type
Article
- DOI
10.7554/eLife.61189