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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Sies, Helmut / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred

IMPACT FACTOR 2017: 3.022

CiteScore 2017: 2.81

SCImago Journal Rank (SJR) 2017: 1.562
Source Normalized Impact per Paper (SNIP) 2017: 0.705

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Volume 393, Issue 10


Functional and structural insights into astacin metallopeptidases

F. Xavier Gomis-Rüth
  • Corresponding author
  • Proteolysis Lab, Molecular Biology Institute of Barcelona, CSIC, Barcelona Science Park, Helix Building, c/Baldiri Reixac, 15-21, E-08028 Barcelona, Spain
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  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Sergio Trillo-Muyo
  • Proteolysis Lab, Molecular Biology Institute of Barcelona, CSIC, Barcelona Science Park, Helix Building, c/Baldiri Reixac, 15-21, E-08028 Barcelona, Spain
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Walter Stöcker
  • Corresponding author
  • Institute of Zoology, Cell and Matrix Biology, Johannes Gutenberg University, Johannes-von-Müller-Weg 6, D-55128 Mainz, Germany
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  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2012-09-08 | DOI: https://doi.org/10.1515/hsz-2012-0149


The astacins are a family of multi-domain metallopeptidases with manifold functions in metabolism. They are either secreted or membrane-anchored and are regulated by being synthesized as inactive zymogens and also by co-localizing protein inhibitors. The distinct family members consist of N-terminal signal peptides and pro-segments, zinc-dependent catalytic domains, further downstream extracellular domains, transmembrane anchors, and cytosolic domains. The catalytic domains of four astacins and the zymogen of one of these have been structurally characterized and shown to comprise compact ∼200-residue zinc-dependent moieties divided into an N-terminal and a C-terminal sub-domain by an active-site cleft. Astacins include an extended zinc-binding motif (HEXXHXXGXXH) which includes three metal ligands and groups them into the metzincin clan of metallopeptidases. In mature, unbound astacins, a conserved tyrosine acts as an additional zinc ligand, which is swung out upon substrate or inhibitor binding in a ‘tyrosine switch’ motion. Other characteristic structural elements of astacin catalytic domains are three large α-helices and a five-stranded β-sheet, as well as two or three disulfide bonds. The N-terminal pro-segments are variable in length and rather unstructured. They inhibit the catalytic zinc following an ‘aspartate-switch’ mechanism mediated by an aspartate embedded in a conserved motif (FXGD). Removal of the pro-segment uncovers a deep and extended active-site cleft, which in general shows preference for aspartate residues in the specificity pocket (S1′). Furthermore, astacins undergo major rearrangement upon activation within an ‘activation domain,’ and show a slight hinge movement when binding substrates or inhibitors. In this review, we discuss the overall architecture of astacin catalytic domains and their involvement in function and zymogenic activation.

Keywords: bone morphogenetic protein; catalytic domain; meprin; metzincin; tolloid; zinc metallopeptidase

About the article

F. Xavier Gomis-Rüth

F. Xavier Gomis-Rüth performed his PhD on protein crystallography under supervision of Wolfram Bode in the department of Robert Huber at the Max Planck Institute of Biochemistry (MPIB) in Martinsried (Germany) in 1992. Post doctoral stays followed at the Autonomous University of Barcelona, the MPIB, and the Molecular Biology Institute of Barcelona (IBMB) of the Spanish Research Council (CSIC), where he became a tenured research scientist in 2000. Since 2008, he has been a Research Professor at CSIC. He is the PI of the Proteolysis Lab at the Department of Structural Biology of the IBMB and author of over 100 publications in the field.

Sergio Trillo-Muyo

Sergio Trillo-Muyo studied human biology at the Pompeu Fabra University of Barcelona, Spain, and obtained his BSc in 2006. In 2008, he obtained an MSc in Biochemistry and Molecular Biology at the Autonomous University of Barcelona in Bellaterra, Spain. He is currently a PhD student in the Proteolysis Lab at the Department of Structural Biology of the Molecular Biology Institute of Barcelona, which is part of the Spanish Research Council (CSIC).

Walter Stöcker

Walter Stöcker studied chemistry and biology at the University of Munich, Germany. After receiving his doctoral degree in Munich in 1984, he was a scientific assistant at the Institute of Zoology, University of Heidelberg, Germany, and did research as a visiting scientist at the Harvard Medical School, Boston, MA, USA, and the Max Planck Institute of Biochemistry, Martinsried, Germany. He received his habilitation in biology from the University of Heidelberg in 1992, and became Associate Professor of Zoology at the University of Münster, Germany in 1996. Since 2003, he has been a full professor and chair at the University of Mainz, Germany. His research focuses on the structure and function of astacin-like zinc peptidases and their interactions in the proteolytic web.

Corresponding authors

Received: 2012-03-09

Accepted: 2012-04-18

Published Online: 2012-09-08

Published in Print: 2012-10-01

Citation Information: , Volume 393, Issue 10, Pages 1027–1041, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/hsz-2012-0149.

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