Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPs

Mol Cell. 1997 Dec;1(1):47-57. doi: 10.1016/s1097-2765(00)80006-4.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • CCAAT-Enhancer-Binding Proteins*
  • CHO Cells / enzymology
  • Cloning, Molecular
  • Cricetinae
  • DNA Mutational Analysis
  • DNA, Complementary
  • DNA-Binding Proteins / metabolism*
  • Endopeptidases / genetics*
  • Endopeptidases / metabolism*
  • Gene Expression Regulation, Enzymologic
  • Genes, Reporter
  • Genetic Complementation Test
  • Humans
  • Luciferases
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / metabolism
  • Molecular Sequence Data
  • Mutation / physiology
  • Nuclear Proteins / metabolism*
  • Sequence Homology, Amino Acid
  • Sterol Regulatory Element Binding Protein 1
  • Transcription Factors*
  • Transfection


  • CCAAT-Enhancer-Binding Proteins
  • DNA, Complementary
  • DNA-Binding Proteins
  • Membrane Proteins
  • Nuclear Proteins
  • SREBF1 protein, human
  • Sterol Regulatory Element Binding Protein 1
  • Transcription Factors
  • Luciferases
  • Endopeptidases
  • Metalloendopeptidases
  • SREBP site 2 protease

Associated data

  • GENBANK/AF019611
  • GENBANK/AF019612