Expanding Members and Roles of the Calpain Superfamily and Their Genetically Modified Animals

Abstract

Abstract:Calpains are intracellular Ca 2+ -dependent cysteine proteases (Clan CA, family C02, EC 3.4.22.17) found in almost all eukaryotes and some bacteria. Calpains display limited proteolytic activity at neutral pH, proteolysing substrates to transform and modulate their structures and activities, and are therefore called "modulator proteases". The human genome has 15 genes that encode a calpain-like protease domain, generating diverse calpain homologues that possess combinations of several functional domains such as Ca 2+ -binding domains and Zn-finger domains. The importance of the physiological roles of calpains is reflected in the fact that particular defects in calpain functionality cause a variety of deficiencies in many different organisms, including lethality, muscular dystrophies, lissencephaly, and tumorigenesis. In this review, the unique characteristics of this distinctive protease superfamily are introduced in terms of genetically modified animals, some of which are animal models of calpain deficiency diseases.

The calpain system and diabetes

“…Micro ( )-calpain and milli (m)-calpain, which are the two most thoroughly studied isoforms [15][16][17][18]. Micro ( )-calpain and milli (m)-calpain are called the conventional calpains and all other calpains are called as unconventional.…”

Molecular Evolution Within Protease Family C2, or Calpains

“…Calpain function has been investigated by both genetic and cell-biological routes (review: Sorimachi et al, 2010). To understand the physiological function of calpain, targeted deletion, and more recently the conditional deletion of calpain genes have been performed.…”

“…Calpain homologues from protozoan, plant, C. elegans, and fungi lack calmodulin-like domain, and thus it seems likely that the proposed cysteine protease-calmodulin gene fusion leading to the classical calpain structure (Croall & DeMartino, 1991;Goll et al, 2003;Sorimachi et al, 2010) occurred exclusively within the animal lineage. Even similar functional units such as EF-hand module evolutionary gained by different ways.…”

“…Calpains were also considered to participate in chromosome rearrangements during mitosis (Schollmeyer, 1988), microtubule assembly and disassembly (Billger et al, 1988), intracellular signaling, motility, and vesicle traffic (Choi et al, 1997;Huttenlocher et al, 1997;Lu et al, 2002;Li & Iyengar, 2002). In mammals and plants it is clear that calpains are of critical importance for development (Wang et al, 2003;Dutt et al, 2006;Sorimachi et al, 2010). Furthermore, impaired calpain activity due to mutations or misregulation of the calpains has been implicated in a variety of pathological conditions including muscular dystrophy, ischemia, diabetes mellitus, cancer, and neurodegenerative disease (Tidball & Spencer, 2000;Huang & Wang, 2001;Crocker et al, 2003;Mamoune et al, 2003;Suzuki et al, 2004;Zatz & Starling, 2005).…”

Post-translational control of Myc function during differentiation

“…25 Numerous proteins have been identified as calpain substrates including cytoskeletal proteins and transcription factors. 26 Given the diversity of …”