Structure of a site-2 protease family intramembrane metalloprotease

Liang Feng, Hanchi Yan, Zhuoru Wu, Nieng Yan, Zhe Wang, Philip D. Jeffrey, Yigong Shi

Research output: Contribution to journalArticlepeer-review

197 Scopus citations


Regulated intramembrane proteolysis by members of the site-2 protease (S2P) family is an important signaling mechanism conserved from bacteria to humans. Here we report the crystal structure of the transmembrane core domain of an S2P metalloprotease from Methanocaldococcus jannaschii. The protease consists of six transmembrane segments, with the catalytic zinc atom coordinated by two histidine residues and one aspartate residue ∼14 angstroms into the lipid membrane surface. The protease exhibits two distinct conformations in the crystals. In the closed conformation, the active site is surrounded by transmembrane helices and is impermeable to substrate peptide; water molecules gain access to zinc through a polar, central channel that opens to the cytosolic side. In the open conformation, transmembrane helices α1 and α6 separate from each other by 10 to 12 angstroms, exposing the active site to substrate entry. The structure reveals how zinc embedded in an integral membrane protein can catalyze peptide cleavage.

Original languageEnglish (US)
Pages (from-to)1608-1612
Number of pages5
Issue number5856
StatePublished - Dec 7 2007

All Science Journal Classification (ASJC) codes

  • General


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