Calpain 1 large subunit (CAPN1) (CAPN1)

The Calpain 1 large subunit (CAPN1), also known as the 80 kDa catalytic subunit of μ-calpain, forms a heterodimer with the common 28 kDa regulatory subunit (CAPNS1) to create the calcium-dependent cysteine protease calpain-1, which performs limited proteolysis rather than wholesale degradation of substrates. This enzyme is ubiquitously expressed and activated by micromolar concentrations of calcium (~30-60 μM for half-maximal activity), triggering conformational changes that align the catalytic triad (Cys, His, Asn) in its protease core and enable cleavage of targets involved in cytoskeletal remodeling, cell migration, and signal transduction pathways. Structurally, it features a multi-domain organization including protease domains IIa/IIb, domain III, and a penta-EF-hand (PEF) domain for subunit dimerization and additional calcium binding, with up to ten calcium ions cooperating in activation. In disease contexts, dysregulated calpain-1 activity contributes to cancer progression, metastasis, and chemotherapeutic resistance by modulating cell signaling and motility. Therapeutic efforts focus on small-molecule inhibitors that disrupt the PEF domain-mediated heterodimerization or block the active site, though challenges arise from the enzyme's broad expression and the need for localized calcium spikes in vivo to avoid toxicity. Crystal structures of calpain-1 and related isoforms reveal auto-inhibitory mechanisms resolved by calcium binding, informing drug design.

Other names

μ-calpain large subunitcalpain-1 large subunit80 kDa subunit of μ-calpain

Inhibition of heterodimerization between large and small subunits, Interference with calcium-dependent activation, Active site inhibition