Structural Insights into the Unique Activation Mechanisms of a Non-classical Calpain and Its Disease-Causing Variants (Cell Reports)

Velez et al. report the crystal structure of the calpain-5 protease core (CAPN5-PC). Sequence- and structure-based phylogenetic analysis reveals that CAPN5-PC contains three elongated loops compared to classical calpains. One loop contains a hyperactivating mutation that causes neovascular inflammatory vitreoretinopathy, revealing a function in this region for regulating proteolytic activity.