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 language | English |
|---|---|
| Pages (from-to) | 2199-2213 |
| Number of pages | 15 |
| Journal | Biochimica et Biophysica Acta - Molecular Basis of Disease |
| Volume | 1864 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 2018 Jun 1 |
Fingerprint
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Molecular Biology
Cite this
}
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, 01.06.2018, p. 2199-2213.Research output: Contribution to journal › Article
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 - 2018/6/1
Y1 - 2018/6/1
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
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 -