ß-dystroglycan is regulated by a balance between WWP1-mediated degradation and protection from WWP1 by dystrophin and utrophin.
Biochim Biophys Acta Mol Basis Dis
; 1864(6 Pt A): 2199-2213, 2018 06.
Article
em En
| MEDLINE
| ID: mdl-29635000
ABSTRACT
Dystroglycan is a ubiquitous membrane protein that functions as a mechanical connection between the extracellular matrix and cytoskeleton. In skeletal muscle, dystroglycan plays an indispensable role in regulating muscle regeneration; a malfunction in dystroglycan is associated with muscular dystrophy. The regulation of dystroglycan stability is poorly understood. Here, we report that WWP1, a member of NEDD4 E3 ubiquitin ligase family, promotes ubiquitination and subsequent degradation of ß-dystroglycan. Our results indicate that dystrophin and utrophin protect ß-dystroglycan from WWP1-mediated degradation by competing with WWP1 for the shared binding site at the cytosolic tail of ß-dystroglycan. In addition, we show that a missense mutation (arginine 440 to glutamine) in WWP1-which is known to cause muscular dystrophy in chickens-increases the ubiquitin ligase-mediated ubiquitination of both ß-dystroglycan and WWP1. The R440Q missense mutation in WWP1 decreases HECT domain-mediated intramolecular interactions to relieve autoinhibition of the enzyme. Our results provide new insight into the regulation of ß-dystroglycan degradation by WWP1 and other Nedd4 family members and improves our understanding of dystroglycan-related disorders.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Distrofina
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Ubiquitina-Proteína Ligases
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Distroglicanas
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Utrofina
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Distrofias Musculares
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article