Molecular interaction between fukutin and POMGnT1 in the glycosylation pathway of alpha-dystroglycan.

Abstract

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.

• Authors: Hui Xiong, Kazuhiro Kobayashi, Masaji Tachikawa, Hiroshi Manya, Satoshi Takeda, Tomohiro Chiyonobu, Nobuhiro Fujikake, Fan Wang, Akemi Nishimoto, Glenn E Morris, Yoshitaka Nagai, Motoi Kanagawa, Tamao Endo, Tatsushi Toda
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 350 Issue 4 Pg. 935-41 (Dec 01 2006) ISSN: 0006-291X [Print] United States
• PMID: 17034757 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DAG1 protein, human
• Proteins
• Dystroglycans
• Fcmd protein, mouse
• Transferases
• N-Acetylglucosaminyltransferases
• protein O-mannose beta-1,2-N-acetylglucosaminyltransferase

Topics

• Animals
• COS Cells
• Chlorocebus aethiops
• Dystroglycans (metabolism)
• Glycosylation
• Humans
• Mice
• N-Acetylglucosaminyltransferases (metabolism)
• Protein Binding
• Protein Interaction Mapping
• Proteins (metabolism)
• Signal Transduction (physiology)
• Transferases