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

3 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

Fingerprint

Utrophin
Dystroglycans
Dystrophin
Muscular Dystrophies
Ubiquitination
Missense Mutation
Ubiquitin-Protein Ligases
Ligases
Ubiquitin
Glutamine
Cytoskeleton
Extracellular Matrix
Arginine
Regeneration
Membrane Proteins
Skeletal Muscle

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology

Cite this

@article{7e3b176e18f744aab299dfae15fa2021,
title = "β-dystroglycan is regulated by a balance between WWP1-mediated degradation and protection from WWP1 by dystrophin and utrophin",
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.",
author = "Cho, {Eun Bee} and Wonjin Yoo and Yoon, {Sungjoo Kim} and Yoon, {Jong Bok}",
year = "2018",
month = "6",
doi = "10.1016/j.bbadis.2018.04.001",
language = "English",
volume = "1864",
pages = "2199--2213",
journal = "Biochimica et Biophysica Acta - Molecular Basis of Disease",
issn = "0925-4439",
publisher = "Elsevier",
number = "6",

}

β-dystroglycan is regulated by a balance between WWP1-mediated degradation and protection from WWP1 by dystrophin and utrophin. / Cho, Eun Bee; Yoo, Wonjin; Yoon, Sungjoo Kim; Yoon, Jong Bok.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1864, No. 6, 06.2018, p. 2199-2213.

Research output: Contribution to journalArticle

TY - JOUR

T1 - β-dystroglycan is regulated by a balance between WWP1-mediated degradation and protection from WWP1 by dystrophin and utrophin

AU - Cho, Eun Bee

AU - Yoo, Wonjin

AU - Yoon, Sungjoo Kim

AU - Yoon, Jong Bok

PY - 2018/6

Y1 - 2018/6

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85045307016&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85045307016&partnerID=8YFLogxK

U2 - 10.1016/j.bbadis.2018.04.001

DO - 10.1016/j.bbadis.2018.04.001

M3 - Article

C2 - 29635000

AN - SCOPUS:85045307016

VL - 1864

SP - 2199

EP - 2213

JO - Biochimica et Biophysica Acta - Molecular Basis of Disease

JF - Biochimica et Biophysica Acta - Molecular Basis of Disease

SN - 0925-4439

IS - 6

ER -