Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 5, Pages E679-E688Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1615141114
Keywords
O-glycopeptidase; metallopeptidase; glycoprotein; O-glycosylation
Categories
Funding
- Canadian Institutes of Health Research (CIHR) [MOP-130305]
- GlycoNet National Centre of Excellence
- CIHR
- Natural Sciences and Engineering Research Council of Canada [NSERC 2014-05218]
- NSERC
- National Research Council Canada
- Canadian Institutes of Health Research
- Province of Saskatchewan
- Western Economic Diversification Canada
- University of Saskatchewan
- DOE Office of Biological and Environmental Research
- National Institutes of HealthNational Institutes of Health, National Center for Research Resources, Biomedical Technology Program [P41RR001209]
- National Institute of General Medical Sciences
- [R24 GM098791]
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The vast majority of proteins are posttranslationally altered, with the addition of covalently linked sugars (glycosylation) being one of the most abundant modifications. However, despite the hydrolysis of protein peptide bonds by peptidases being a process essential to all life on Earth, the fundamental details of how peptidases accommodate posttranslational modifications, including glycosylation, has not been addressed. Through biochemical analyses and X-ray crystallo-graphic structures we show that to hydrolyze their substrates, three structurally related metallopeptidases require the specific recognition of O-linked glycan modifications via carbohydrate-specific subsites immediately adjacent to their peptidase catalytic machinery. The three peptidases showed selectivity for different glycans, revealing protein-specific adaptations to particular glycan modifications, yet always cleaved the peptide bond immediately preceding the glycosylated residue. This insight builds upon the paradigm of how peptidases recognize substrates and provides a molecular understanding of glycoprotein degradation.
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