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| Título: | A novel family of soluble minimal scaffolds provides structural insight into the catalytic domains of integral-membrane metallopeptidases |
Autor: | López-Pelegrín, Mar CSIC; Cerdà-Costa, Núria CSIC; Canals, Albert CSIC ORCID ; Arolas, Joan L. CSIC; Gomis-Rüth, F. Xavier CSIC ORCID | Palabras clave: | Enzyme mechanisms Enzyme structure Membrane enzymes Metalloprotease Molecular modeling Catalytic domains |
Fecha de publicación: | 2013 | Editor: | American Society for Biochemistry and Molecular Biology | Citación: | Journal of Biological Chemistry 288(29): 21279-21294 (2013) | Resumen: | 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 hitherto unseen in MPs: intra-molecular, through an extended tail, in proabylysin, and crosswise inter-molecular, through a helix swap, in projannalysin. In addition, structural and sequence comparisons, as well as phylogenetic and bioinformatics analyses, revealed large similarity with MPs of the gluzincin tribe such as thermolysin, leukotriene A4 hydrolase relatives, and cowrins. Interestingly, gluzincins mostly have a glutamate as third characteristic zinc ligand while minigluzincins have a histidine. Sequence and structure similarity further allowed us to ascertain that minigluzincins are very similar to the catalytic domains of integral-membrane MPs of 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. | Descripción: | et al. | Versión del editor: | http://dx.doi.org/10.1074/jbc.M113.476580 | URI: | http://hdl.handle.net/10261/88129 | DOI: | 10.1074/jbc.M113.476580 | ISSN: | 0021-9258 | E-ISSN: | 1083-351X |
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| LopezPelegrin_JBC_2013_corrMs.pdf | 8,04 MB | Adobe PDF |  Visualizar/Abrir |
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