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Structure of collagenase G reveals a chew-and-digest mechanism of bacterial collagenolysis

Abstract

Collagen constitutes one-third of body protein in humans, reflecting its extensive role in health and disease. Of similar importance, therefore, are the idiosyncratic proteases that have evolved for collagen remodeling. The most efficient collagenases are those that enable clostridial bacteria to colonize their host tissues; but despite intense study, the structural and mechanistic basis of these enzymes has remained elusive. Here we present the crystal structure of collagenase G from Clostridium histolyticum at 2.55-Å resolution. By combining the structural data with enzymatic and mutagenesis studies, we derive a conformational two-state model of bacterial collagenolysis, in which recognition and unraveling of collagen microfibrils into triple helices, as well as unwinding of the triple helices, are driven by collagenase opening and closing.

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Figure 1: Domain organization and architecture of ColG.
Figure 2: The activator domain is necessary for the degradation of collagen.
Figure 3: Mapping the peptidase active site.
Figure 4: Unified processing model of triple-helical and microfibrillar collagen.

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Acknowledgements

We thank F. Hesse (Roche, Penzberg) for providing plasmids; P. Klemm for cloning an activator-deletion construct; S. Ginzinger and M. Sippl for help with canonical electron density expansion; L. Moroder and H. Nagase for valuable discussions; our anonymous reviewers for helpful suggestions and clarifications; staff at the synchrotron facilities ESRF, DESY and BESSY for help in data collection; and the Austrian Science Fund (FWF) for funding (H.B., project P20582).

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U.E. performed experiments (protein production, enzymological measurements, crystallization, X-ray data collection and structure determination), analyzed data and prepared the manuscript; E.S. performed experiments (enzymological measurements), analyzed data and prepared the manuscript; D.N. performed experiments (crystal harvesting and X-ray data collection); H.B. devised the project, helped with structure solution, analyzed data and wrote the paper.

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Correspondence to Hans Brandstetter.

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Eckhard, U., Schönauer, E., Nüss, D. et al. Structure of collagenase G reveals a chew-and-digest mechanism of bacterial collagenolysis. Nat Struct Mol Biol 18, 1109–1114 (2011). https://doi.org/10.1038/nsmb.2127

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