Calpain-1

Calpain-1, also known as mu-calpain or CAPN1, is a calcium-dependent, non-lysosomal cysteine protease that belongs to the calpain superfamily. It is a ubiquitously expressed intracellular protease involved in numerous cellular processes, including signal transduction, cytoskeletal remodeling, cell proliferation, differentiation, apoptosis, and necrosis.

Calpain-1 is a heterodimer, consisting of a large catalytic subunit (approximately 80 kDa) and a small regulatory subunit (approximately 30 kDa). The large subunit contains the cysteine protease domain, which is responsible for proteolytic activity, as well as calcium-binding domains. The small subunit stabilizes the large subunit and enhances its calcium sensitivity.

Activation of calpain-1 requires calcium binding. Upon an increase in intracellular calcium concentration, calpain-1 undergoes autolysis, which further enhances its activity. Calpain-1 activity is regulated by endogenous inhibitors, primarily calpastatin, which binds to and inhibits both calpain-1 and calpain-2.

Calpain-1 cleaves a wide variety of substrates, including cytoskeletal proteins, signaling molecules, and membrane receptors. Its involvement in cytoskeletal remodeling affects cell shape, adhesion, and motility. The proteolytic processing of signaling molecules by calpain-1 can modulate downstream signaling pathways involved in cell growth, differentiation, and apoptosis.

Dysregulation of calpain-1 activity has been implicated in various pathological conditions, including neurodegenerative diseases, muscular dystrophies, cardiovascular diseases, and cancer. Specifically, aberrant calpain-1 activation can contribute to neuronal damage in stroke and Alzheimer's disease, muscle fiber degradation in muscular dystrophy, and inflammatory responses in cardiovascular disease. Therefore, calpain-1 is a potential therapeutic target for these conditions.