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Structural basis of laminin binding to the LARGE glycans on dystroglycan

Dystroglycan is a highly glycosylated extracellular matrix receptor with essential functions in skeletal muscle and the nervous system. Reduced matrix binding by α-dystroglycan (α-DG) due to perturbed glycosylation is a pathological feature of several forms of muscular dystrophy. Like-acetylglucosam...

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Autores principales: Briggs, David C., Yoshida-Moriguchi, Takako, Zheng, Tianqing, Venzke, David, Anderson, Mary, Strazzulli, Andrea, Moracci, Marco, Yu, Liping, Hohenester, Erhard, Campbell, Kevin P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5030134/
https://www.ncbi.nlm.nih.gov/pubmed/27526028
http://dx.doi.org/10.1038/nchembio.2146
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author Briggs, David C.
Yoshida-Moriguchi, Takako
Zheng, Tianqing
Venzke, David
Anderson, Mary
Strazzulli, Andrea
Moracci, Marco
Yu, Liping
Hohenester, Erhard
Campbell, Kevin P.
author_facet Briggs, David C.
Yoshida-Moriguchi, Takako
Zheng, Tianqing
Venzke, David
Anderson, Mary
Strazzulli, Andrea
Moracci, Marco
Yu, Liping
Hohenester, Erhard
Campbell, Kevin P.
author_sort Briggs, David C.
collection PubMed
description Dystroglycan is a highly glycosylated extracellular matrix receptor with essential functions in skeletal muscle and the nervous system. Reduced matrix binding by α-dystroglycan (α-DG) due to perturbed glycosylation is a pathological feature of several forms of muscular dystrophy. Like-acetylglucosaminyltransferase (LARGE) synthesizes the matrix-binding heteropolysaccharide [-glucuronic acid-β1,3-xylose-α1,3-](n). Using a dual exoglycosidase digestion, we confirm that this polysaccharide is present on native α-DG from skeletal muscle. The atomic details of matrix binding were revealed by a high-resolution crystal structure of laminin G-like (LG) domains 4–5 of laminin α2 bound to a LARGE-synthesized oligosaccharide. A single glucuronic acid-β1,3-xylose disaccharide repeat straddles a Ca(2+) ion in the LG4 domain, with oxygen atoms from both sugars replacing Ca(2+)-bound water molecules. The chelating binding mode accounts for the high affinity of this protein-carbohydrate interaction. These results reveal a novel mechanism of carbohydrate recognition and provide a structural framework for elucidating the mechanisms underlying muscular dystrophy.
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spelling pubmed-50301342017-02-15 Structural basis of laminin binding to the LARGE glycans on dystroglycan Briggs, David C. Yoshida-Moriguchi, Takako Zheng, Tianqing Venzke, David Anderson, Mary Strazzulli, Andrea Moracci, Marco Yu, Liping Hohenester, Erhard Campbell, Kevin P. Nat Chem Biol Article Dystroglycan is a highly glycosylated extracellular matrix receptor with essential functions in skeletal muscle and the nervous system. Reduced matrix binding by α-dystroglycan (α-DG) due to perturbed glycosylation is a pathological feature of several forms of muscular dystrophy. Like-acetylglucosaminyltransferase (LARGE) synthesizes the matrix-binding heteropolysaccharide [-glucuronic acid-β1,3-xylose-α1,3-](n). Using a dual exoglycosidase digestion, we confirm that this polysaccharide is present on native α-DG from skeletal muscle. The atomic details of matrix binding were revealed by a high-resolution crystal structure of laminin G-like (LG) domains 4–5 of laminin α2 bound to a LARGE-synthesized oligosaccharide. A single glucuronic acid-β1,3-xylose disaccharide repeat straddles a Ca(2+) ion in the LG4 domain, with oxygen atoms from both sugars replacing Ca(2+)-bound water molecules. The chelating binding mode accounts for the high affinity of this protein-carbohydrate interaction. These results reveal a novel mechanism of carbohydrate recognition and provide a structural framework for elucidating the mechanisms underlying muscular dystrophy. 2016-08-15 2016-10 /pmc/articles/PMC5030134/ /pubmed/27526028 http://dx.doi.org/10.1038/nchembio.2146 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Briggs, David C.
Yoshida-Moriguchi, Takako
Zheng, Tianqing
Venzke, David
Anderson, Mary
Strazzulli, Andrea
Moracci, Marco
Yu, Liping
Hohenester, Erhard
Campbell, Kevin P.
Structural basis of laminin binding to the LARGE glycans on dystroglycan
title Structural basis of laminin binding to the LARGE glycans on dystroglycan
title_full Structural basis of laminin binding to the LARGE glycans on dystroglycan
title_fullStr Structural basis of laminin binding to the LARGE glycans on dystroglycan
title_full_unstemmed Structural basis of laminin binding to the LARGE glycans on dystroglycan
title_short Structural basis of laminin binding to the LARGE glycans on dystroglycan
title_sort structural basis of laminin binding to the large glycans on dystroglycan
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5030134/
https://www.ncbi.nlm.nih.gov/pubmed/27526028
http://dx.doi.org/10.1038/nchembio.2146
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