Molecular interaction between fukutin and POMGnT1 in the glycosylation pathway of alpha-dystroglycan.
The recent identification of mutations in genes encoding demonstrated or putative glycosyltransferases has revealed a novel mechanism for congenital muscular dystrophy. Hypoglycosylated alpha-dystroglycan (alpha-DG) is commonly seen in Fukuyama-type congenital muscular dystrophy (FCMD), muscle-eye-brain disease (MEB), Walker-Warburg syndrome (WWS), and Large(myd) mice. POMGnT1 and POMTs, the gene products responsible for MEB and WWS, respectively, synthesize unique O-mannose sugar chains on alpha-DG. The function of fukutin, the gene product responsible for FCMD, remains undetermined. Here we show that fukutin co-localizes with POMGnT1 in the Golgi apparatus. Direct interaction between fukutin and POMGnT1 was confirmed by co-immunoprecipitation and two-hybrid analyses. The transmembrane region of fukutin mediates its localization to the Golgi and participates in the interaction with POMGnT1. Y371C, a missense mutation found in FCMD, retains fukutin in the ER and also redirects POMGnT1 to the ER. Finally, we demonstrate reduced POMGnT1 enzymatic activity in transgenic knock-in mice carrying the retrotransposal insertion in the fukutin gene, the prevalent mutation in FCMD. From these findings, we propose that fukutin forms a complex with POMGnT1 and may modulate its enzymatic activity.
Xiong
Hui
H
Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan.
Kobayashi
Kazuhiro
K
Tachikawa
Masaji
M
Manya
Hiroshi
H
Takeda
Satoshi
S
Chiyonobu
Tomohiro
T
Fujikake
Nobuhiro
N
Wang
Fan
F
Nishimoto
Akemi
A
Morris
Glenn E
GE
Nagai
Yoshitaka
Y
Kanagawa
Motoi
M
Endo
Tamao
T
Toda
Tatsushi
T
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D049030:Dystroglycans / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D051379:Mice; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014166:Transferases
C483081:DAG1 protein, human; D011506:Proteins; D049030:Dystroglycans; C491879:Fcmd protein, mouse; D014166:Transferases; D017351:N-Acetylglucosaminyltransferases; C443106:protein O-mannose beta-1,2-N-acetylglucosaminyltransferase