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

Robert B. Rawson, Nikolai G. Zelenski, Deepak Nijhawan, Jin Ye, Juro Sakai, Mazahir T. Hasan, T. Y. Chang, Michael S. Brown, Joseph L. Goldstein

Research output: Contribution to journalArticle

360 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)47-57
Number of pages11
JournalMolecular cell
Issue number1
StatePublished - Dec 1997


ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this