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Title: Structure of a Site-2 Protease Family Intramembrane Metalloprotease

Abstract

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.

Authors:
; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
959856
Report Number(s):
BNL-82842-2009-JA
Journal ID: ISSN 0193-4511; SCEHDK; TRN: US201016%%1000
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Science; Journal Volume: 318
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; ATOMS; BACTERIA; CLEAVAGE; CRYSTAL STRUCTURE; HISTIDINE; LIPIDS; MEMBRANE PROTEINS; MEMBRANES; PEPTIDES; PROTEOLYSIS; RESIDUES; SUBSTRATES; WATER; ZINC; national synchrotron light source

Citation Formats

Feng,L., Yan, H., Wu, Z., Yan, N., Wang, Z., Jeffrey, P., and Shi, Y. Structure of a Site-2 Protease Family Intramembrane Metalloprotease. United States: N. p., 2007. Web. doi:10.1126/science.1150755.
Feng,L., Yan, H., Wu, Z., Yan, N., Wang, Z., Jeffrey, P., & Shi, Y. Structure of a Site-2 Protease Family Intramembrane Metalloprotease. United States. doi:10.1126/science.1150755.
Feng,L., Yan, H., Wu, Z., Yan, N., Wang, Z., Jeffrey, P., and Shi, Y. Mon . "Structure of a Site-2 Protease Family Intramembrane Metalloprotease". United States. doi:10.1126/science.1150755.
@article{osti_959856,
title = {Structure of a Site-2 Protease Family Intramembrane Metalloprotease},
author = {Feng,L. and Yan, H. and Wu, Z. and Yan, N. and Wang, Z. and Jeffrey, P. and Shi, Y.},
abstractNote = {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.},
doi = {10.1126/science.1150755},
journal = {Science},
number = ,
volume = 318,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}