Identification and modelling of a GT-A fold in the α-dystroglycan glycosylating enzyme LARGE1

Manuela Bozzi, Benedetta Righino, Davide Pirolli, Francesca Sciandra, Andrea Brancaccio, Maria Cristina De Rosa, Maria Giulia Bigotti

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

LARGE xylosyl- and glucuronyltransferase 1 (LARGE1)is an enzyme responsible for the final steps of the post-translational modifications of dystroglycan (DG), a membrane receptor that links the cytoskeleton with the extracellular matrix in skeletal muscle and in a variety of other tissues. LARGE1 acts by adding the repeating disaccharide unit [-3Xyl-α1,3GlcAβ1-] to the extracellular portion of the DG complex (α-DG); defects in the LARGE1 gene result in an aberrant glycosylation of α-DG and consequent impairment of its binding to laminin, eventually affecting the connection between the cell and the extracellular environment. In skeletal muscle, this leads to degeneration of the muscular tissue and muscular dystrophy. So far, a few missense mutations have been identified within the LARGE1 protein and linked to congenital muscular dystrophy and, since no structural information is available on this enzyme, our understanding of the molecular mechanisms underlying these pathologies is still very limited. Here, we generated a 3D model structure of the two catalytic domains of LARGE1, combining different molecular modelling approaches. Furthermore, by using molecular dynamics simulations we analyzed the effect on the structure and stability of the first catalytic domain of the pathological missense mutation S331F that gives rise to a severe form of muscle-eye-brain disease.
Original languageEnglish
Pages (from-to)3145-3156
Number of pages12
JournalJournal of Chemical Information and Modeling
DOIs
Publication statusPublished - 2020

Keywords

  • dystroglycan
  • folding prediction
  • molecular dynamics simulations
  • molecular modelling

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