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Title: The Crystal Structure of GXGD Membrane Protease FlaK

Abstract

The GXGD proteases are polytopic membrane proteins with catalytic activities against membrane-spanning substrates that require a pair of aspartyl residues. Representative members of the family include preflagellin peptidase, type 4 prepilin peptidase, presenilin and signal peptide peptidase. Many GXGD proteases are important in medicine. For example, type 4 prepilin peptidase may contribute to bacterial pathogenesis, and mutations in presenilin are associated with Alzheimer's disease. As yet, there is no atomic-resolution structure in this protease family. Here we report the crystal structure of FlaK, a preflagellin peptidase from Methanococcus maripaludis, solved at 3.6 {angstrom} resolution. The structure contains six transmembrane helices. The GXGD motif and a short transmembrane helix, helix 4, are positioned at the centre, surrounded by other transmembrane helices. The crystal structure indicates that the protease must undergo conformational changes to bring the GXGD motif and a second essential aspartyl residue from transmembrane helix 1 into close proximity for catalysis. A comparison of the crystal structure with models of presenilin derived from biochemical analysis reveals three common transmembrane segments that are similarly arranged around the active site. This observation reinforces the idea that the prokaryotic and human proteases are evolutionarily related. The crystal structure presented here provides a frameworkmore » for understanding the mechanism of the GXGD proteases, and may facilitate the rational design of inhibitors that target specific members of the family.« less

Authors:
; ; ;
Publication Date:
Research Org.:
BROOKHAVEN NATIONAL LABORATORY (BNL)
Sponsoring Org.:
USDOE SC OFFICE OF SCIENCE (SC)
OSTI Identifier:
1041673
Report Number(s):
BNL-97351-2012-JA
Journal ID: ISSN 0028-0836; TRN: US201212%%776
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nature; Journal Volume: 475; Journal Issue: 7357
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; BIOCHEMISTRY; BIOLOGY; BIOPHYSICS; CATALYSIS; CONFORMATIONAL CHANGES; CRYSTAL STRUCTURE; DESIGN; MEDICINE; MEMBRANE PROTEINS; MEMBRANES; MOLECULAR BIOLOGY; MUTATIONS; PATHOGENESIS; PEPTIDES; RESIDUES; RESOLUTION; SUBSTRATES; TARGETS

Citation Formats

J Hu, Y Xue, S Lee, and Y Ha. The Crystal Structure of GXGD Membrane Protease FlaK. United States: N. p., 2011. Web. doi:10.1038/nature10218.
J Hu, Y Xue, S Lee, & Y Ha. The Crystal Structure of GXGD Membrane Protease FlaK. United States. doi:10.1038/nature10218.
J Hu, Y Xue, S Lee, and Y Ha. Sat . "The Crystal Structure of GXGD Membrane Protease FlaK". United States. doi:10.1038/nature10218.
@article{osti_1041673,
title = {The Crystal Structure of GXGD Membrane Protease FlaK},
author = {J Hu and Y Xue and S Lee and Y Ha},
abstractNote = {The GXGD proteases are polytopic membrane proteins with catalytic activities against membrane-spanning substrates that require a pair of aspartyl residues. Representative members of the family include preflagellin peptidase, type 4 prepilin peptidase, presenilin and signal peptide peptidase. Many GXGD proteases are important in medicine. For example, type 4 prepilin peptidase may contribute to bacterial pathogenesis, and mutations in presenilin are associated with Alzheimer's disease. As yet, there is no atomic-resolution structure in this protease family. Here we report the crystal structure of FlaK, a preflagellin peptidase from Methanococcus maripaludis, solved at 3.6 {angstrom} resolution. The structure contains six transmembrane helices. The GXGD motif and a short transmembrane helix, helix 4, are positioned at the centre, surrounded by other transmembrane helices. The crystal structure indicates that the protease must undergo conformational changes to bring the GXGD motif and a second essential aspartyl residue from transmembrane helix 1 into close proximity for catalysis. A comparison of the crystal structure with models of presenilin derived from biochemical analysis reveals three common transmembrane segments that are similarly arranged around the active site. This observation reinforces the idea that the prokaryotic and human proteases are evolutionarily related. The crystal structure presented here provides a framework for understanding the mechanism of the GXGD proteases, and may facilitate the rational design of inhibitors that target specific members of the family.},
doi = {10.1038/nature10218},
journal = {Nature},
number = 7357,
volume = 475,
place = {United States},
year = {Sat Dec 31 00:00:00 EST 2011},
month = {Sat Dec 31 00:00:00 EST 2011}
}