Structure of a Site-2 Protease Family Intramembrane Metalloprotease

Journal Article · Mon Jan 01 04:00:00 EST 2007 · Science

DOI:https://doi.org/10.1126/science.1150755· OSTI ID:959856

Feng, L; Yan, H; Wu, Z; Yan, N; Wang, Z; Jeffrey, P; Shi, Y

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 {approx}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 {alpha}1 and {alpha}6 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.

• Research Organization: Brookhaven National Laboratory (BNL) National Synchrotron Light Source
• Sponsoring Organization: Doe - Office Of Science
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 959856
• Report Number(s): BNL--82842-2009-JA
• Journal Information: Science, Journal Name: Science Vol. 318; ISSN 0193-4511; ISSN SCEHDK
• Country of Publication: United States
• Language: English

Related Subjects

36 MATERIALS SCIENCE
ATOMS
BACTERIA
CLEAVAGE
CRYSTAL STRUCTURE
HISTIDINE
LIPIDS
MEMBRANE PROTEINS
MEMBRANES
PEPTIDES
PROTEOLYSIS
RESIDUES
SUBSTRATES
WATER
ZINC
national synchrotron light source