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

Svensson Birkedal, Gabriel LU ; Awad, Wael; Håkansson, Maria; Mani, Katrin LU and Logan, Derek (2012) In Journal of Biological Chemistry 287(17). p.14040-14051
Abstract
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
287
issue
17
pages
14040 - 14051
publisher
ASBMB
external identifiers
  • wos:000303996300058
  • pmid:22351761
  • scopus:84859986516
ISSN
1083-351X
DOI
10.1074/jbc.M111.322487
language
English
LU publication?
yes
id
a327bb7c-1c97-46de-bb60-659bbf1ed62a (old id 2366474)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/22351761?dopt=Abstract
date added to LUP
2012-03-02 12:57:19
date last changed
2017-04-23 03:04:39
@article{a327bb7c-1c97-46de-bb60-659bbf1ed62a,
  abstract     = {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.},
  author       = {Svensson Birkedal, Gabriel and Awad, Wael and Håkansson, Maria and Mani, Katrin and Logan, Derek},
  issn         = {1083-351X},
  language     = {eng},
  number       = {17},
  pages        = {14040--14051},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Crystal structure of N-glycosylated human glypican-1 core protein: Structure of two loops evolutionarily conserved in vertebrate glypican-1.},
  url          = {http://dx.doi.org/10.1074/jbc.M111.322487},
  volume       = {287},
  year         = {2012},
}