Esther SCHÖNAUER & Ulrich ECKHARD (shared first authorship)
 & 

Structural basis for activity regulation and substrate preference of clostridial collagenases G, H, and T
Esther Schönauer*, Ulrich Eckhard*, and Hans Brandstetter
*Both authors contributed equally toward the completion of the work

Abstract
Clostridial collagenases are among the most efficient enzymes to degrade collagen, the most predominant protein in the animal kingdom. The interest in these collagenases is high due to their multiple biotechnological and medical applications, and their potential as drug targets, as their inhibition could block the colonization and infiltration by pathogenic clostridia. We present crystal structures of the peptidases of the clostridial collagenases ColG, ColH and ColT. The comparison of unliganded and liganded structures reveal a quaternary subdomain dynamics, which is modulated in ColH by an aspartate switch that binds to the catalytic zinc. We further identified a novel calcium binding site in proximity to the catalytic zinc. Both ions are required for full activity, explaining why calcium critically affects their enzymatic activity. In addition, our studies reveal that loops close to the active site serve as a characteristic substrate selectivity filter. These elements explain the distinct peptidolytic and collagenolytic activities of these enzymes and provide a rational framework to understand and optimize the isoform dependent collagenase activities.

The open access article can be found  here.

Reviewed by Chiara Cabrele