title: Structural basis for oligosaccharide recognition of misfolded glycoproteins by OS-9 in ER-associated degradation.
abstract: Misfolded glycoproteins are translocated from endoplasmic reticulum (ER) into the cytosol for proteasome-mediated degradation. A mannose-6-phosphate receptor homology (MRH) domain is commonly identified in a variety of proteins and, in the case of OS-9 and XTP3-B, is involved in glycoprotein ER-associated degradation (ERAD). Trimming of outermost α1,2-linked mannose on C-arm of high-mannose-type glycan and binding of processed α1,6-linked mannosyl residues by the MRH domain are critical steps in guiding misfolded glycoproteins to enter ERAD. Here we report the crystal structure of a human OS-9 MRH domain (OS-9(MRH)) complexed with α3,α6-mannopentaose. The OS-9(MRH) has a flattened β-barrel structure with a characteristic P-type lectin fold and possesses distinctive double tryptophan residues in the oligosaccharide-binding site. Our crystallographic result in conjunction with nuclear magnetic resonance (NMR) spectroscopic and biochemical results provides structural insights into the mechanism whereby OS-9 specifically recognizes Manα1,6Manα1,6Man residues on the processed C-arm through the continuous double tryptophan (WW) motif.
authors.affiliation: Structural Glycobiology Team, RIKEN Advanced Science Institute, Saitama 351-0198, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Satoh
authors.forename: Yang
authors.initials: Y
authors.lastname: Chen
authors.forename: Dan
authors.initials: D
authors.lastname: Hu
authors.forename: Shinya
authors.initials: S
authors.lastname: Hanashima
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Yamaguchi
mesh_terms: D002236:Carbohydrate Conformation; D018360:Crystallography, X-Ray; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006023:Glycoproteins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D037102:Lectins / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D009844:Oligosaccharides / Q000737:chemistry* / Q000378:metabolism*; D017510:Protein Folding; D017527:Receptor, IGF Type 2 / Q000737:chemistry / Q000378:metabolism
chemical_list: C531192:ERLEC1 protein, human; D006023:Glycoproteins; D037102:Lectins; D009363:Neoplasm Proteins; C098898:OS9 protein, human; D009844:Oligosaccharides; D017527:Receptor, IGF Type 2