What is Calycin Superfamily?

 Calpains constitute a family of intracellular Ca(2+)-regulated cysteine proteases that are indispensable in the regulation of a wide variety of cellular functions. The improper activation of calpain causes lethality or various disorders, such as muscular dystrophies and tumor formation.

Calycin superfamily is divided into 3 main classes including muscle calpain-3 (also termed p94), stomach nCl-2 and nCl-4, and the lens calpains Lp82 and Lp85.

--p94

mRNA of p94, which has a significant sequence similarity to the conventional calpain large subunits, is abundantly expressed only in skeletal muscle. In addition to this specific expression, p94 is distinct from conventional calpains in that it contains three unique regions showing no similarity to conventional calpain subunits. As the activity of calpain is regulated by calcium ions essential for cellular signal transduction, calpain is believed to regulate signal transduction by modulating the activity and the structure of various proteins, e.g., protein kinase C, phospholipase C or transcription factors.

--nCL-2 and nCL-4

nCL-2/calpain 8 is predominantly expressed in the stomach, where it appears to be involved in membrane trafficking in the gastric surface mucus cells (pit cells). Another tissue-specific calpain, nCL-4, the expression of which is predominantly in the digestive tract, also occurs in the stomach. It is reported to be downregulated in a subset of gastric cancer patients and is involved in the suppression of tumorigenesis.

Fig 1 A model of the disassembly of the COPI subcomplex with proteolysis by nCL-2

--Lp82 and Lp85

Two isozymes of calpain 3: Lp82 and Lp85, which belong to calycin superfamily, may be the major calpains involved in murine cataractogenesis. The loss of alpha3Cx46 leads to increased levels of Ca(2+) ions, and this increase activates the CAPN3 isoform, Lp82/85, which results in the formation of a nuclear cataract.

Fig 2 Representative lens pathways leading to calpain activation

Calycin superfamily is the target for drug discovery, which provides a new research idea for drug intervention therapy of cataract, cancers, etc.