Like-acetylglucosaminyltransferase (LARGE)-dependent modification of dystroglycan at Thr-317/319 is required for laminin binding and arenavirus infection

Yuji Hara; Motoi Kanagawa; Stefan Kunz; Takako Yoshida-Moriguchi; Jakob S Satz; Yvonne M Kobayashi; Zihan Zhu; Steven J Burden; Michael B. A Oldstone; Kevin P Campbell

doi:10.1073/pnas.1114836108

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Like-acetylglucosaminyltransferase (LARGE)-dependent modification of dystroglycan at Thr-317/319 is required for laminin binding and arenavirus infection

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Like-acetylglucosaminyltransferase (LARGE)-dependent modification of dystroglycan at Thr-317/319 is required for laminin binding and arenavirus infection

Yuji Hara, Motoi Kanagawa, Stefan Kunz, Takako Yoshida-Moriguchi, Jakob S Satz, Yvonne M Kobayashi, Zihan Zhu, Steven J Burden, Michael B. A Oldstone and Kevin P Campbell

Proceedings of the National Academy of Sciences - PNAS, Vol.108(42), pp.17426-17431

10/18/2011

DOI: 10.1073/pnas.1114836108

PMCID: PMC3198351

PMID: 21987822

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Abstract

α-dystroglycan is a highly O-glycosylated extracellular matrix receptor that is required for anchoring of the basement membrane to the cell surface and for the entry of Old World arenaviruses into cells. Like-acetylglucosaminyltransferase (LARGE) is a key molecule that binds to the N-terminal domain of α-dystroglycan and attaches ligand-binding moieties to phosphorylated O-mannose on α-dystroglycan. Here we show that the LARGE modification required for laminin- and virus-binding occurs on specific Thr residues located at the extreme N terminus of the mucin-like domain of α-dystroglycan. Deletion and mutation analyses demonstrate that the ligand-binding activity of α-dystroglycan is conferred primarily by LARGE modification at Thr-317 and -319, within the highly conserved first 18 amino acids of the mucin-like domain. The importance of these paired residues in laminin-binding and clustering activity on myoblasts and in arenavirus cell entry is confirmed by mutational analysis with full-length dystroglycan. We further demonstrate that a sequence of five amino acids, Thr317ProThr319ProVal, contains phosphorylated O-glycosylation and, when modified by LARGE is sufficient for laminin-binding. Because the N-terminal region adjacent to the paired Thr residues is removed during posttranslational maturation of dystroglycan, our results demonstrate that the ligand-binding activity resides at the extreme N terminus of mature α-dystroglycan and is crucial for α-dystroglycan to coordinate the assembly of extracellular matrix proteins and to bind arenaviruses on the cell surface.

Biological Sciences

Muscular Dystrophy

posttranslational modification

glycoprotein–ligand interaction

Lassa fever virus

phosphorylation of O-mannosyl glycan

Details

Title: Subtitle: Like-acetylglucosaminyltransferase (LARGE)-dependent modification of dystroglycan at Thr-317/319 is required for laminin binding and arenavirus infection
Creators: Yuji Hara - The Howard Hughes Medical Institute, Departments of
Motoi Kanagawa - The Howard Hughes Medical Institute, Departments of
Stefan Kunz - Institute of Microbiology
Takako Yoshida-Moriguchi - The Howard Hughes Medical Institute, Departments of
Jakob S Satz - The Howard Hughes Medical Institute, Departments of
Yvonne M Kobayashi - The Howard Hughes Medical Institute, Departments of
Zihan Zhu - The Howard Hughes Medical Institute, Departments of
Steven J Burden - Molecular Neurobiology Program, The Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine
Michael B. A Oldstone - Department of Immunology and Microbial Science
Kevin P Campbell - The Howard Hughes Medical Institute, Departments of
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.108(42), pp.17426-17431
DOI: 10.1073/pnas.1114836108
PMID: 21987822
PMCID: PMC3198351
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Language: English
Date published: 10/18/2011
Academic Unit: Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute
Record Identifier: 9984020781802771

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