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J Biol Chem. 2013 Jul 19;288(29):21279-94. doi: 10.1074/jbc.M113.476580. Epub 2013 Jun 3.

A novel family of soluble minimal scaffolds provides structural insight into the catalytic domains of integral membrane metallopeptidases.

Author information

1
Proteolysis Laboratory, Department of Structural Biology, Molecular Biology Institute of Barcelona, Consejo Superior de Investigaciones Científicas, c/Baldiri Reixac, 15-21, 08028 Barcelona, Spain.

Abstract

In the search for structural models of integral-membrane metallopeptidases (MPs), we discovered three related proteins from thermophilic prokaryotes, which we grouped into a novel family called "minigluzincins." We determined the crystal structures of the zymogens of two of these (Pyrococcus abyssi proabylysin and Methanocaldococcus jannaschii projannalysin), which are soluble and, with ∼100 residues, constitute the shortest structurally characterized MPs to date. Despite relevant sequence and structural similarity, the structures revealed two unique mechanisms of latency maintenance through the C-terminal segments previously unseen in MPs as follows: intramolecular, through an extended tail, in proabylysin, and crosswise intermolecular, through a helix swap, in projannalysin. In addition, structural and sequence comparisons revealed large similarity with MPs of the gluzincin tribe such as thermolysin, leukotriene A4 hydrolase relatives, and cowrins. Noteworthy, gluzincins mostly contain a glutamate as third characteristic zinc ligand, whereas minigluzincins have a histidine. Sequence and structural similarity further allowed us to ascertain that minigluzincins are very similar to the catalytic domains of integral membrane MPs of the MEROPS database families M48 and M56, such as FACE1, HtpX, Oma1, and BlaR1/MecR1, which are provided with trans-membrane helices flanking or inserted into a minigluzincin-like catalytic domain. In a time where structural biochemistry of integral-membrane proteins in general still faces formidable challenges, the minigluzincin soluble minimal scaffold may contribute to our understanding of the working mechanisms of these membrane MPs and to the design of novel inhibitors through structure-aided rational drug design approaches.

KEYWORDS:

Catalytic Domain; Enzyme Mechanisms; Enzyme Structure; Enzymology; Membrane Enzymes; Metallopeptidase; Metalloprotease; Molecular Model; Molecular Modeling; Zymogen

PMID:
23733187
PMCID:
PMC3774397
DOI:
10.1074/jbc.M113.476580
[Indexed for MEDLINE]
Free PMC Article
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