Journal article
N-terminal domain on dystroglycan enables LARGE1 to extend matriglycan on α-dystroglycan and prevents muscular dystrophy
eLife, Vol.12, e82811
02/01/2023
DOI: 10.7554/eLife.82811
PMCID: PMC9917425
PMID: 36723429
Abstract
Dystroglycan (DG) requires extensive post-translational processing and
-glycosylation to function as a receptor for extracellular matrix (ECM) proteins containing laminin-G-like (LG) domains. Matriglycan is an elongated polysaccharide of alternating xylose (Xyl) and glucuronic acid (GlcA) that binds with high-affinity to ECM proteins with LG-domains and is uniquely synthesized on α-dystroglycan (α-DG) by like-acetylglucosaminyltransferase-1 (LARGE1). Defects in the post-translational processing or
-glycosylation of α-DG that result in a shorter form of matriglycan reduce the size of α-DG and decrease laminin binding, leading to various forms of muscular dystrophy. Previously, we demonstrated that Protein O-Mannose Kinase (POMK) is required for LARGE1 to generate full-length matriglycan on α-DG (~150-250 kDa) (Walimbe et al., 2020). Here, we show that LARGE1 can only synthesize a short, non-elongated form of matriglycan in mouse skeletal muscle that lacks the DG N-terminus (α-DGN), resulting in a ~100-125 kDa α-DG. This smaller form of α-DG binds laminin and maintains specific force but does not prevent muscle pathophysiology, including reduced force production after eccentric contractions or abnormalities in the neuromuscular junctions. Collectively, our study demonstrates that α-DGN, like POMK, is required for LARGE1 to extend matriglycan to its full mature length on α-DG and thus prevent muscle pathophysiology.
Details
- Title: Subtitle
- N-terminal domain on dystroglycan enables LARGE1 to extend matriglycan on α-dystroglycan and prevents muscular dystrophy
- Creators
- Hidehiko Okuma - University of IowaJeffrey M Hord - University of IowaIshita Chandel - University of IowaDavid Venzke - Department of Department of Molecular Physiology and BiophysicsPhysiology and Biophysics, Howard Hughes Medical Institute, University of Iowa, Iowa City, United StatesMary E Anderson - Department of Molecular Physiology and Biophysics, Howard Hughes Medical Institute, University of Iowa, Iowa City, United StatesAmeya S Walimbe - University of IowaSoumya Joseph - University of IowaZeita Gastel - Department of Molecular Physiology and Biophysics, Howard Hughes Medical Institute, University of Iowa, Iowa City, United StatesYuji Hara - University of ShizuokaFumiaki Saito - Teikyo UniversityKiichiro Matsumura - Teikyo UniversityKevin P Campbell - Department of Molecular Physiology and Biophysics, Howard Hughes Medical Institute, University of Iowa, Iowa City, United States
- Resource Type
- Journal article
- Publication Details
- eLife, Vol.12, e82811
- DOI
- 10.7554/eLife.82811
- PMID
- 36723429
- PMCID
- PMC9917425
- NLM abbreviation
- Elife
- eISSN
- 2050-084X
- Grant note
- 1U54NS053672 / Paul D. Wellstone Muscular Dystrophy Specialized Research Center
- Language
- English
- Date published
- 02/01/2023
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984365159702771
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