Document Detail


The crystal structure of GXGD membrane protease FlaK.
MedLine Citation:
PMID:  21765428     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 Å 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.
Authors:
Jian Hu; Yi Xue; Sangwon Lee; Ya Ha
Related Documents :
21859938 - Carbapenems: past, present, and future.
21805238 - Insights from bacterial subtilases into the mechanisms of intramolecular chaperone-medi...
12853468 - The structure of the cell cycle protein cdc14 reveals a proline-directed protein phosph...
21660658 - Cathepsin proteases in toxoplasma gondii.
19269068 - Structure-based virtual screening approach to identify novel classes of ptp1b inhibitors.
17696448 - Inhibition of trypsin by condensed tannins and wine.
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2011-07-17
Journal Detail:
Title:  Nature     Volume:  475     ISSN:  1476-4687     ISO Abbreviation:  Nature     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-07-28     Completed Date:  2011-08-03     Revised Date:  2014-10-19    
Medline Journal Info:
Nlm Unique ID:  0410462     Medline TA:  Nature     Country:  England    
Other Details:
Languages:  eng     Pagination:  528-31     Citation Subset:  IM    
Data Bank Information
Bank Name/Acc. No.:
PDB/3S0X
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Archaeal Proteins / chemistry*
Crystallography, X-Ray
Membrane Proteins / chemistry
Methanococcus / chemistry*
Models, Molecular*
Peptide Hydrolases / chemistry*
Presenilin-1 / chemistry
Protein Structure, Tertiary
Grant Support
ID/Acronym/Agency:
P30 EB009998/EB/NIBIB NIH HHS; P41 RR012408/RR/NCRR NIH HHS; P41 RR015301/RR/NCRR NIH HHS; R01 GM082839/GM/NIGMS NIH HHS; R01 GM101136/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Archaeal Proteins; 0/Membrane Proteins; 0/Presenilin-1; EC 3.4.-/Peptide Hydrolases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  A two-step chemical mechanism for ribosome-catalysed peptide bond formation.
Next Document:  Photoentrainment and pupillary light reflex are mediated by distinct populations of ipRGCs.