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Structure of a Site-2 Protease Family Intramembrane Metalloprotease
Liang Feng,1*Hanchi Yan,1*Zhuoru Wu,1*Nieng Yan,1Zhe Wang,2Philip D. Jeffrey,1Yigong Shi1
Regulated intramembrane proteolysis by members of the site-2protease (S2P) family is an important signaling mechanism conservedfrom bacteria to humans. Here we report the crystal structureof the transmembrane core domain of an S2P metalloprotease fromMethanocaldococcus jannaschii. The protease consists of sixtransmembrane segments, with the catalytic zinc atom coordinatedby two histidine residues and one aspartate residue 14 angstromsinto the lipid membrane surface. The protease exhibits two distinctconformations in the crystals. In the closed conformation, theactive site is surrounded by transmembrane helices and is impermeableto substrate peptide; water molecules gain access to zinc througha polar, central channel that opens to the cytosolic side. Inthe open conformation, transmembrane helices 1 and 6 separatefrom each other by 10 to 12 angstroms, exposing the active siteto substrate entry. The structure reveals how zinc embeddedin an integral membrane protein can catalyze peptide cleavage.
1 Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ 08544, USA. 2 Department of Chemistry, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
* These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail: ygshi{at}princeton.edu
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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 
1 and 
To whom correspondence should be addressed. E-mail: 
