β-dystroglycan is regulated by a balance between WWP1-mediated degradation and protection from WWP1 by dystrophin and utrophin

Eun Bee Cho, Wonjin Yoo, Sungjoo Kim Yoon, Jong Bok Yoon

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 β-dystroglycan. Our results indicate that dystrophin and utrophin protect β-dystroglycan from WWP1-mediated degradation by competing with WWP1 for the shared binding site at the cytosolic tail of β-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 β-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 β-dystroglycan degradation by WWP1 and other Nedd4 family members and improves our understanding of dystroglycan-related disorders.

Original languageEnglish
Pages (from-to)2199-2213
Number of pages15
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1864
Issue number6
DOIs
Publication statusPublished - 2018 Jun

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology

Fingerprint Dive into the research topics of 'β-dystroglycan is regulated by a balance between WWP1-mediated degradation and protection from WWP1 by dystrophin and utrophin'. Together they form a unique fingerprint.

  • Cite this