The glucuronyltransferase B4GAT1 is required for initiation of LARGE-mediated α-dystroglycan functional glycosylation

Tobias Willer; Kei-Ichiro Inamori; David Venzke; Corinne Harvey; Greg Morgensen; Yuji Hara; Daniel Beltrán Valero de Bernabé; Liping Yu; Kevin M Wright; Kevin P Campbell

doi:10.7554/eLife.03941

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The glucuronyltransferase B4GAT1 is required for initiation of LARGE-mediated α-dystroglycan functional glycosylation

Journal article

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Peer reviewed

The glucuronyltransferase B4GAT1 is required for initiation of LARGE-mediated α-dystroglycan functional glycosylation

Tobias Willer, Kei-Ichiro Inamori, David Venzke, Corinne Harvey, Greg Morgensen, Yuji Hara, Daniel Beltrán Valero de Bernabé, Liping Yu, Kevin M Wright and Kevin P Campbell

eLife, Vol.3, e03941

10/03/2014

DOI: 10.7554/eLife.03941

PMCID: PMC4227050

PMID: 25279699

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Abstract

Dystroglycan is a cell membrane receptor that organizes the basement membrane by binding ligands in the extracellular matrix. Proper glycosylation of the α-dystroglycan (α-DG) subunit is essential for these activities, and lack thereof results in neuromuscular disease. Currently, neither the glycan synthesis pathway nor the roles of many known or putative glycosyltransferases that are essential for this process are well understood. Here we show that FKRP, FKTN, TMEM5 and B4GAT1 (formerly known as B3GNT1) localize to the Golgi and contribute to the O-mannosyl post-phosphorylation modification of α-DG. Moreover, we assigned B4GAT1 a function as a xylose β1,4-glucuronyltransferase. Nuclear magnetic resonance studies confirmed that a glucuronic acid β1,4-xylose disaccharide synthesized by B4GAT1 acts as an acceptor primer that can be elongated by LARGE with the ligand-binding heteropolysaccharide. Our findings greatly broaden the understanding of α-DG glycosylation and provide mechanistic insight into why mutations in B4GAT1 disrupt dystroglycan function and cause disease.

Phosphorylation

Cell Line

Xylose - metabolism

Magnetic Resonance Spectroscopy

Humans

Dystroglycans - metabolism

Glucuronic Acid - metabolism

Substrate Specificity

Mutant Proteins - metabolism

Glycosylation

Mutation - genetics

N-Acetylglucosaminyltransferases - metabolism

Protein Transport

Animals

N-Acetylglucosaminyltransferases - deficiency

Embryo, Mammalian - cytology

Models, Biological

Golgi Apparatus - metabolism

Mice

Subcellular Fractions - enzymology

Fibroblasts - metabolism

Details

Title: Subtitle: The glucuronyltransferase B4GAT1 is required for initiation of LARGE-mediated α-dystroglycan functional glycosylation
Creators: Tobias Willer - Department of Molecular Physiology and Biophysics, University of Iowa, Carver College of Medicine, Iowa City, United States
Kei-Ichiro Inamori - Department of Molecular Physiology and Biophysics, University of Iowa, Carver College of Medicine, Iowa City, United States
David Venzke - Department of Molecular Physiology and Biophysics, University of Iowa, Carver College of Medicine, Iowa City, United States
Corinne Harvey - Department of Molecular Physiology and Biophysics, University of Iowa, Carver College of Medicine, Iowa City, United States
Greg Morgensen - Department of Molecular Physiology and Biophysics, University of Iowa, Carver College of Medicine, Iowa City, United States
Yuji Hara - Department of Molecular Physiology and Biophysics, University of Iowa, Carver College of Medicine, Iowa City, United States
Daniel Beltrán Valero de Bernabé - Department of Molecular Physiology and Biophysics, University of Iowa, Carver College of Medicine, Iowa City, United States
Liping Yu - Medical Nuclear Magnetic Resonance Facility, University of Iowa, Carver College of Medicine, Iowa City, United States
Kevin M Wright - Vollum Institute, Oregon Health and Science University, Portland, United States
Kevin P Campbell - Department of Molecular Physiology and Biophysics, University of Iowa, Carver College of Medicine, Iowa City, United States
Resource Type: Journal article
Publication Details: eLife, Vol.3, e03941
DOI: 10.7554/eLife.03941
PMID: 25279699
PMCID: PMC4227050
NLM abbreviation: Elife
ISSN: 2050-084X
eISSN: 2050-084X
Publisher: England
Grant note: U54 NS053672 / NINDS NIH HHS 1U54NS053672 / NINDS NIH HHS Howard Hughes Medical Institute P30 DK054759 / NIDDK NIH HHS RC2 NS069521 / NINDS NIH HHS
Language: English
Date published: 10/03/2014
Academic Unit: Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Biochemistry and Molecular Biology; Medicine Administration
Record Identifier: 9984020866302771

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