Molecular basis of proteolytic cleavage regulation by the extracellular matrix receptor dystroglycan
Open accessPublished version of a preprint
Abstract
The dystrophin-glycoprotein-complex (DGC), anchored by the transmembrane protein dystroglycan, functions to mechanically link the extracellular matrix and actin cytoskeleton. Breaking this connection is associated with diseases such as muscular dystrophy, yet cleavage of dystroglycan by matrix-metalloproteinases (MMPs) remains an understudied mechanism to disrupt the DGC. We determined the crystal structure of the membrane-adjacent domain (amino acids 491-722) of E. coli expressed human dystroglycan to understand MMP cleavage regulation. The structural model includes tandem immunoglobulin-like (IGL) and sperm/enterokinase/agrin-like (SEAL) domains, which support proteolysis in diverse receptors to facilitate mechanotransduction, membrane protection, and viral entry. The structure reveals a C-terminal extension that buries the MMP site by packing into a hydrophobic pocket, a unique mechanism of MMP cleavage regulation. We further demonstrate structure-guided and disease-associated mutations disrupt proteolytic regulation using a cell-surface proteolysis assay. Thus disrupted proteolysis is a potentially relevant mechanism for "breaking" the DGC link to contribute to disease pathogenesis.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Self-citationThe evolution of the dystroglycan complex, a major mediator of muscle integrity
Adams, J. C., & Brancaccio, A. (2015) · Biology Open · doi:10.1242/bio.012468 · Cited by 35 · see citing works
Flagged first, then by citations
- Authors
- Anderson, M. J. M., Hayward, A. N., Smiley, A. T., Shi, K., Pawlak, M. R., Aird, E. J., Grant, E., Greenberg, L., Aihara, H., Evans, R. L., Ulens, C., & Gordon, W. R.
- Affiliations
- University of Minnesota (US)
- Corresponding author
- Gordon, Wendy R.
- ORCID
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2024-11
- Volume
- 32
- Issue
- 11
- Pages
- 1984-1996.e5
- ISSN
- 0969-2126 (ISSN-L)
- PMC
- PMC11560575
- OpenAlex
- W4402677483
- Cited by
- 5
- References
- 2
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1
- FWCI
- 0.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 371 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Structure (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- American Heart Association (17PRE33330000, T32 GM132029)
- National Institute of General Medical Sciences (R35 GM119483, R35 GM118047)
- U.S. Department of Energy (DE-AC02-06CH11357, P30 GM124165)
- NIH (T32 GM132029, T32 AR007512, T32 GM008244)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- dystroglycan, dystrophin-glycoprotein complex, matrix metalloproteinase cleavage, extracellular matrix, actin cytoskeleton, immunoglobulin-like domains, C-terminal extension, hydrophobic pocket, crystal structure, muscular dystrophy, mechanotransduction, disease-associated mutations
- MeSH terms
- Protein Domains, Binding Sites, Extracellular Matrix, Humans, Models, Molecular, Mutation, Protein Binding, Crystallography, X-Ray, Matrix Metalloproteinases, Dystroglycans, Proteolysis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
