What is the role of hcast 3-25 in the regulation of calpain-1 activity?

Calpain-1 is a calcium-dependent protease involved in various cellular processes, including migration, proliferation, and apoptosis. Its activity is tightly regulated by calpastatin, a specific protein inhibitor. However, in some diseases, calpain-1 becomes over-activated, leading to cellular damage. This study investigates a novel calpastatin variant, hcast 3-25, which lacks the inhibitory domains but contains the L-domain and a portion of the C-terminal tail. The study explores how hcast 3-25 affects calpain-1 activity.

hcast 3-25 acts as a positive modulator of calpain-1 activity. It prevents the degradation of calpain-1 by activated calpain-1 molecules and blocks the binding of inhibitory calpastatins to calpain-1. This results in the protection of calpain-1 from inactivation and degradation, allowing it to maintain its catalytic activity. The study concludes that hcast 3-25 is a novel member of the calpain/calpastatin system that modulates calpain-1 activity through a mechanism different from classical inhibition.