Killing Two Angry Birds with One Stone: Autophagy Activation by Inhibiting Calpains in Neurodegenerative Diseases and Beyond

Figure 1

Domain composition and structure of calpain-1, CSS1, and CAST. Conventional classical calpains are present as a large protease unit, such as the here depicted calpain-1, and the calpain small subunit 1 (CSS1). Both share a C-terminal Ca²⁺-binding penta-EF-hand (PEF) domain. Calpain-1 further contains an N-terminal proteolytic CysPc domain, consisting of core domains PC1 and PC2, which also bind Ca²⁺ ions. Amino acid positions of the catalytic triad of calpain-1 are indicated by vertical white lines. In addition, a calpain-like β-sandwich domain (CBSW) is located between the CysPc and the PEF domain. CSS1 features, moreover, an N-terminal glycine-rich (GR) hydrophobic domain. The endogenous inhibitor calpastatin (CAST) contains four structurally flexible inhibitory domains (ID1-4) of which each can inhibit one calpain molecule. Illustrations of calpain-1, CSS1, and CAST are based on data retrieved from the UniProt database (respective identifiers P07384-1, P04632-1, and P20810-1).