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Functional O‐Mannosylation of α‐Dystroglycan: Trisaccharide‐phospho‐ribitol Primed for Matriglycan Addition
Author(s) -
Praissman Jeremy Lawrence,
Willer Tobias,
Sheikh M Osman,
Toi Ants,
Chitayat David,
Lin YungYao,
Lee Hane,
Stalnaker Stephanie,
Wang Shuo,
Prabhakar Pradeep,
Nelson Stanley F,
Stemple Derek L,
Moore Steven A,
Moremen Kelley W,
Campbell Kevin P,
Wells Lance
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.lb121
Subject(s) - glycan , dystroglycan , glycosyltransferase , ribitol , glycosylation , chemistry , biochemistry , microbiology and biotechnology , computational biology , biology , gene , laminin , enzyme , glycoprotein , cell
Multiple glycosyltransferases are essential for the proper modification of alpha‐dystroglycan, with defects in the encoding genes causing congenital/limb‐girdle muscular dystrophy. Here we elucidate the structure of an O‐mannose‐initiated glycan on alpha‐dystroglycan that is required to generate its ECM‐binding polysaccharide. We show that the functional glycan contains a novel ribitol structure that links the phosphotrisaccharide on the protein to xylose. Further we demonstrate that ISPD is a CDP‐ribitol pyrophosphorylase for generation of the activated donor. We also identify TMEM5 as a UDP‐xylosyl transferase, and defects in human patients, as well as a zebrafish model, result in muscular dystrophy in combination with abnormal brain development. Alpha‐dystroglycan from human cell lines lacking the post‐ribitol glycosyltransferases is unable to bind ECM proteins. Thus, we propose a novel structure – a ribitol extending from a phosphotrisaccharide – for the moiety on which TMEM5, B4GAT1, and LARGE act to generate the functional receptor for ECM proteins. Support or Funding Information This work was supported in part by grants from NIGMS/NIH (R01GM111939 to LW, P01GM107012, KWM and LW co‐PIs), technology resource grants from NIGMS/NIH (P41GM103490, KWM and LW co‐PIs and P41GM103390, KWM, PI), a Paul D. Wellstone Muscular Dystrophy Cooperative Research Center Grant (1U54NS053672, KPC, SAM and TW), a MDA grant (238219, KPC and TW) and an ARRA Go Grant (1 RC2 NS069521‐01, KPC and TW). KPC is an investigator of the Howard Hughes Medical Institute.Model of alpha‐dystroglycan functional glycosylation with (X) indicating the final link that this work filled in.