Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPs.
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.
Rawson
R B
RB
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas 75235, USA.
Zelenski
N G
NG
Nijhawan
D
D
Ye
J
J
Sakai
J
J
Hasan
M T
MT
Chang
T Y
TY
Brown
M S
MS
Goldstein
J L
JL
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
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