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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:
; ; ;  [1]
  1. (Yale-MED)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NSFOTHERUNIVERSITYDOE - BASIC ENERGY SCIENCESNIH
OSTI Identifier:
1023670
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nature; Journal Volume: 475; Journal Issue: 07, 2011
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; BIOCHEMISTRY; BIOPHYSICS; CATALYSIS; CONFORMATIONAL CHANGES; CRYSTAL STRUCTURE; DESIGN; HUMAN POPULATIONS; MEDICINE; MEMBRANE PROTEINS; MEMBRANES; MOLECULAR BIOLOGY; MUTATIONS; PATHOGENESIS; PEPTIDES; RESIDUES; RESOLUTION; SIGNALS; SUBSTRATES; TARGETS

Citation Formats

Hu, Jian, Xue, Yi, Lee, Sangwon, and Ha, Ya. The crystal structure of GXGD membrane protease FlaK. United States: N. p., 2011. Web. doi:10.1038/nature10218.
Hu, Jian, Xue, Yi, Lee, Sangwon, & Ha, Ya. The crystal structure of GXGD membrane protease FlaK. United States. doi:10.1038/nature10218.
Hu, Jian, Xue, Yi, Lee, Sangwon, and Ha, Ya. Tue . "The crystal structure of GXGD membrane protease FlaK". United States. doi:10.1038/nature10218.
@article{osti_1023670,
title = {The crystal structure of GXGD membrane protease FlaK},
author = {Hu, Jian and Xue, Yi and Lee, Sangwon and Ha, Ya},
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 = 07, 2011,
volume = 475,
place = {United States},
year = {Tue Sep 20 00:00:00 EDT 2011},
month = {Tue Sep 20 00:00:00 EDT 2011}
}