title: Structure of a cholesterol-binding protein deficient in Niemann-Pick type C2 disease.
abstract: Niemann-Pick disease type C2 (NP-C2) is a fatal hereditary disease characterized by accumulation of low-density lipoprotein-derived cholesterol in lysosomes. Here we report the 1.7-A resolution crystal structure of the cholesterol-binding protein deficient in this disease, NPC2, and the characterization of its ligand binding properties. Human NPC2 binds the cholesterol analog dehydroergosterol with submicromolar affinity at both acidic and neutral pH. NPC2 has an Ig-like fold stabilized by three disulfide bonds. The structure of the bovine protein reveals a loosely packed region penetrating from the surface into the hydrophobic core that forms adjacent small cavities with a total volume of approximately 160 A(3). We propose that this region represents the incipient cholesterol-binding site that dilates to accommodate an approximately 740-A(3) cholesterol molecule.
authors.affiliation: Center for Advanced Biotechnology and Medicine, Howard Hughes Medical Institute, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, 679 Hoes Lane, Piscataway, NJ 08854, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Friedland
authors.forename: Heng-Ling
authors.initials: HL
authors.lastname: Liou
authors.forename: Peter
authors.initials: P
authors.lastname: Lobel
authors.forename: Ann M
authors.initials: AM
authors.lastname: Stock
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins; D002417:Cattle; D002784:Cholesterol / Q000737:chemistry; D006224:Cricetinae; D018360:Crystallography, X-Ray; D004220:Disulfides; D004305:Dose-Response Relationship, Drug; D006023:Glycoproteins / Q000737:chemistry* / Q000235:genetics*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D008894:Milk Proteins / Q000737:chemistry* / Q000235:genetics*; D008925:Mites; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009542:Niemann-Pick Diseases / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013261:Sterols / Q000737:chemistry; D033921:Vesicular Transport Proteins
chemical_list: D002352:Carrier Proteins; D004220:Disulfides; D006023:Glycoproteins; D008024:Ligands; D008894:Milk Proteins; C104585:NPC2 protein, human; D013261:Sterols; D033921:Vesicular Transport Proteins; D002784:Cholesterol