Abstract
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.
About the authors
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 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 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.
©2012 by Walter de Gruyter Berlin Boston
