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Crystal structure of full-length N-glycosylated human glypican-1
Structural highlights
DiseaseGPC1_HUMAN Biliary atresia. Associates (via the heparan sulfate side chains) with fibrillar APP-beta amyloid peptides in primitive and classic amyloid plaques and may be involved in the deposition of these senile plaques in the Alzheimer disease (AD) brain. Misprocessing of GPC1 is found in fibroblasts of patients with Niemann-Pick Type C1 disease. This is due to the defective deaminative degradation of heparan sulfate chains. FunctionGPC1_HUMAN Cell surface proteoglycan that bears heparan sulfate. Binds, via the heparan sulfate side chains, alpha-4 (V) collagen and participates in Schwann cell myelination (By similarity). May act as a catalyst in increasing the rate of conversion of prion protein PRPN(C) to PRNP(Sc) via associating (via the heparan sulfate side chains) with both forms of PRPN, targeting them to lipid rafts and facilitating their interaction. Required for proper skeletal muscle differentiation by sequestering FGF2 in lipid rafts preventing its binding to receptors (FGFRs) and inhibiting the FGF-mediated signaling.[1] [2] Publication Abstract from PubMedGlypicans 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-synthesizing 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-labeled 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 A, the first crystal structure of a vertebrate glypican, reveals the complete disulfide bond arrangement of the conserved Cys residues, and it 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. Crystal Structure of N-Glycosylated Human Glypican-1 Core Protein: STRUCTURE OF TWO LOOPS EVOLUTIONARILY CONSERVED IN VERTEBRATE GLYPICAN-1.,Svensson G, Awad W, Hakansson M, Mani K, Logan DT J Biol Chem. 2012 Apr 20;287(17):14040-51. Epub 2012 Feb 20. PMID:22351761[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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