期刊
GLYCOBIOLOGY
卷 26, 期 12, 页码 1284-1296出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/glycob/cww075
关键词
dystroglycan; glycosaminoglycan; laminin binding; LARGE2; proteoglycan
资金
- Paul D. Wellstone Muscular Dystrophy Cooperative Research Center [1U54NS053672]
- University of Georgia College of Pharmacy
Both LARGE1 (formerly LARGE) and its paralog LARGE2 are bifunctional glycosyltransferases with xylosy- and glucuronyltransferase activities, and are capable of synthesizing polymers composed of a repeating disaccharide [-3Xyl alpha 1,3GlcA beta 1-]. Post-translational modification of the O-mannosyl glycan of a-dystroglycan (alpha-DG) with the polysaccharide is essential for it to act as a receptor for ligands in the extracellular matrix (ECM), and both LARGE paralogs contribute to the modification in vivo. LARGE1 and LARGE2 have different tissue distribution profiles and enzymatic properties; however, the functional difference of the homologs remains to be determined, and a-DG is the only known substrate for the modification by LARGE1 or LARGE2. Here we show that LARGE2 can modify proteoglycans (PGs) with the laminin-binding glycan. We found that overexpression of LARGE2, but not LARGE1, mediates the functional modification on the surface of DG(-/-), Pomt1(-/-) and Fktn(-/-) embryonic stem cells. We identified a heparan sulfate-PG glypican-4 as a substrate for the LARGE2-dependent modification by affinity purification and subsequent mass spectrometric analysis. Furthermore, we showed that LARGE2 could modify several additional PGs with the laminin-binding glycan, most likely within the glycosaminoglycan (GAG)-protein linkage region. Our results indicate that LARGE2 can modify PGs with the GAG-like polysaccharide composed of xylose and glucuronic acid to confer laminin binding. Thus, LARGE2 may play a differential role in stabilizing the basement membrane and modifying its functions by augmenting the interactions between laminin globular domain-containing ECM proteins and PGs.
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