title: Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPs.
abstract: We report the cloning of a gene, S2P, that encodes a putative metalloprotease required for intramembrane proteolysis of sterol-regulatory element-binding proteins (SREBPs) at Site-2. SREBPs are membrane-bound transcription factors that activate genes regulating cholesterol metabolism. The active NH2-terminal domains of SREBPs are released from membranes by sequential cleavage at two sites: Site-1, within the lumen of the endoplasmic reticulum; and Site-2, within a transmembrane segment. The human S2P gene was cloned by complementation of mutant CHO cells that cannot cleave SREBPs at Site-2 and are cholesterol auxotrophs. S2P defines a new family of polytopic membrane proteins that contain an HEXXH sequence characteristic of zinc metalloproteases. Mutation of the putative zinc-binding residues abolishes S2P activity. S2P encodes an unusual metalloprotease that cleaves proteins within transmembrane segments.
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas 75235, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Rawson
authors.forename: N G
authors.initials: NG
authors.lastname: Zelenski
authors.forename: D
authors.initials: D
authors.lastname: Nijhawan
authors.forename: J
authors.initials: J
authors.lastname: Ye
authors.forename: J
authors.initials: J
authors.lastname: Sakai
authors.forename: M T
authors.initials: MT
authors.lastname: Hasan
authors.forename: T Y
authors.initials: TY
authors.lastname: Chang
authors.forename: M S
authors.initials: MS
authors.lastname: Brown
authors.forename: J L
authors.initials: JL
authors.lastname: Goldstein
mesh_terms: D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D016466:CHO Cells / Q000201:enzymology; D003001:Cloning, Molecular; D006224:Cricetinae; D004252:DNA Mutational Analysis; D018076:DNA, Complementary; D004268:DNA-Binding Proteins / Q000378:metabolism*; D010450:Endopeptidases / Q000235:genetics* / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D005816:Genetic Complementation Test; D006801:Humans; D008156:Luciferases; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology; D009687:Nuclear Proteins / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014162:Transfection
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D008156:Luciferases; D010450:Endopeptidases; D008666:Metalloendopeptidases; C112686:SREBP site 2 protease