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Crystal structure of N-glycosylated human glypican-1 core protein: Structure of two loops evolutionarily conserved in vertebrate glypican-1.

På svenska

Author

  • Gabriel Svensson Birkedal
  • Wael Awad
  • Maria Håkansson
  • Katrin Mani
  • Derek Logan

Summary, in English

Glypicans are a family of cell-surface proteoglycans that regulate Wnt, hedgehog, bone morphogenetic protein and fibroblast growth factor signaling. Loss-of-function mutations in glypican core proteins and in glycosaminoglycan synthezing enzymes have revealed that glypican core proteins and their glycosaminoglycan chains are important in shaping animal development. Glypican core proteins consist of a stable alpha-helical domain containing 14 conserved Cys residues followed by a glycosaminoglycan attachment domain that becomes exclusively substituted with heparan sulfate (HS) and presumably adopts a random coil conformation. Removal of the alpha-helical domain results in almost exclusive addition of the glycosaminoglycan chondroitin sulfate, suggesting that factors in the alpha-helical domain promote assembly of HS. Glypican-1 is involved in brain development and is one of six members of the vertebrate family of glypicans. We expressed and crystallized N-glycosylated human glypican-1 lacking HS and N-glycosylated glypican-1 lacking the HS attachment domain. The crystal structure of glypican-1 was solved using crystals of selenomethionine labelled glypican-1 core protein lacking the HS domain. No additional electron density was observed for crystals of glypican-1 containing the HS attachment domain, and CD spectra of the two protein species were highly similar. The crystal structure of N- glycosylated human glypican-1 core protein at 2.5 Å, the first crystal structure of a vertebrate glypican, reveals the complete disulfide bond arrangement of the conserved Cys residues, and also extends the structural knowledge of glypicans for one alpha helix and two long loops. Importantly, the loops are evolutionarily conserved in vertebrate glypican-1 and one of them is involved in glycosaminoglycan class determination.

Department/s

Publishing year

2012

Language

English

Pages

14040-14051

Publication/Series

Journal of Biological Chemistry

Volume

287

Issue

17

Document type

Journal article

Publisher

American Society for Biochemistry and Molecular Biology

Topic

  • Medicinal Chemistry

Status

Published

Research group

  • Glycobiology

ISBN/ISSN/Other

  • ISSN: 1083-351X