Calpain-5 (CAPN5)

Calpain-5 (CAPN5) is a member of the calpain family of calcium-dependent cysteine proteases, classified as a non-classical calpain due to its distinct domain structure and regulatory mechanisms[1][3][4]. It is highly expressed in retinal photoreceptor cells, and its activity is regulated by unusually high calcium requirements compared to classical calpains. Disease-causing mutations in CAPN5 lead to hyperactivation and are strongly associated with Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy (ADNIV), a progressive inflammatory and degenerative retinal disorder featuring uveitis, retinal degeneration, neovascularization, and fibrosis[1][3]. Structural analyses reveal that CAPN5 has unique elongated flexible loops, some of which harbor pathogenic mutations, providing insight into substrate specificity and potential avenues for selective inhibition[1][2]. The native biological functions of CAPN5 likely include regulation of protein turnover and cell signaling under high calcium stress, with important roles in retinal and possibly neuronal cells[3]. While there are no drugs presently used to therapeutically target CAPN5, research tools such as E-64 and CAST/B27 peptides can inhibit its proteolytic activity in vitro, and studies are ongoing to develop selective inhibitors for future therapies[1][3].

Other names

Calpain 5CAPN5NCL3nCL-3HTRA3ADNIVCalpain htra-3New calpain 3VRNIcalpain-5testis tissue sperm-binding protein Li 91mP

Irreversible inhibition of proteolytic activity (E-64) Competitive inhibition via peptide binding (CAST/B27)