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N-terminal domain on dystroglycan enables LARGE1 to extend matriglycan on α-dystroglycan and prevents muscular dystrophy

Dystroglycan (DG) requires extensive post-translational processing and O-glycosylation to function as a receptor for extracellular matrix (ECM) proteins containing laminin-G (LG) domains. Matriglycan is an elongated polysaccharide of alternating xylose (Xyl) and glucuronic acid (GlcA) that binds wit...

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Autores principales: Okuma, Hidehiko, Hord, Jeffrey M, Chandel, Ishita, Venzke, David, Anderson, Mary E, Walimbe, Ameya S, Joseph, Soumya, Gastel, Zeita, Hara, Yuji, Saito, Fumiaki, Matsumura, Kiichiro, Campbell, Kevin P
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9917425/
https://www.ncbi.nlm.nih.gov/pubmed/36723429
http://dx.doi.org/10.7554/eLife.82811
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author Okuma, Hidehiko
Hord, Jeffrey M
Chandel, Ishita
Venzke, David
Anderson, Mary E
Walimbe, Ameya S
Joseph, Soumya
Gastel, Zeita
Hara, Yuji
Saito, Fumiaki
Matsumura, Kiichiro
Campbell, Kevin P
author_facet Okuma, Hidehiko
Hord, Jeffrey M
Chandel, Ishita
Venzke, David
Anderson, Mary E
Walimbe, Ameya S
Joseph, Soumya
Gastel, Zeita
Hara, Yuji
Saito, Fumiaki
Matsumura, Kiichiro
Campbell, Kevin P
author_sort Okuma, Hidehiko
collection PubMed
description Dystroglycan (DG) requires extensive post-translational processing and O-glycosylation to function as a receptor for extracellular matrix (ECM) proteins containing laminin-G (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 O-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 an ~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 (ECs) 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.
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spelling pubmed-99174252023-02-11 N-terminal domain on dystroglycan enables LARGE1 to extend matriglycan on α-dystroglycan and prevents muscular dystrophy Okuma, Hidehiko Hord, Jeffrey M Chandel, Ishita Venzke, David Anderson, Mary E Walimbe, Ameya S Joseph, Soumya Gastel, Zeita Hara, Yuji Saito, Fumiaki Matsumura, Kiichiro Campbell, Kevin P eLife Biochemistry and Chemical Biology Dystroglycan (DG) requires extensive post-translational processing and O-glycosylation to function as a receptor for extracellular matrix (ECM) proteins containing laminin-G (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 O-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 an ~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 (ECs) 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. eLife Sciences Publications, Ltd 2023-02-01 /pmc/articles/PMC9917425/ /pubmed/36723429 http://dx.doi.org/10.7554/eLife.82811 Text en © 2023, Okuma et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry and Chemical Biology
Okuma, Hidehiko
Hord, Jeffrey M
Chandel, Ishita
Venzke, David
Anderson, Mary E
Walimbe, Ameya S
Joseph, Soumya
Gastel, Zeita
Hara, Yuji
Saito, Fumiaki
Matsumura, Kiichiro
Campbell, Kevin P
N-terminal domain on dystroglycan enables LARGE1 to extend matriglycan on α-dystroglycan and prevents muscular dystrophy
title N-terminal domain on dystroglycan enables LARGE1 to extend matriglycan on α-dystroglycan and prevents muscular dystrophy
title_full N-terminal domain on dystroglycan enables LARGE1 to extend matriglycan on α-dystroglycan and prevents muscular dystrophy
title_fullStr N-terminal domain on dystroglycan enables LARGE1 to extend matriglycan on α-dystroglycan and prevents muscular dystrophy
title_full_unstemmed N-terminal domain on dystroglycan enables LARGE1 to extend matriglycan on α-dystroglycan and prevents muscular dystrophy
title_short N-terminal domain on dystroglycan enables LARGE1 to extend matriglycan on α-dystroglycan and prevents muscular dystrophy
title_sort n-terminal domain on dystroglycan enables large1 to extend matriglycan on α-dystroglycan and prevents muscular dystrophy
topic Biochemistry and Chemical Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9917425/
https://www.ncbi.nlm.nih.gov/pubmed/36723429
http://dx.doi.org/10.7554/eLife.82811
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