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Acta Medica Okayama Jun 2007Intracellular calcium is a powerful secondary messenger that affects a number of calcium sensors, including calpain, a Ca2+-dependent cysteine protease, and calcineurin,... (Review)
Review
Intracellular calcium is a powerful secondary messenger that affects a number of calcium sensors, including calpain, a Ca2+-dependent cysteine protease, and calcineurin, a Ca2+/calmodulin-dependent protein phosphatase. Maintenance of low basal levels of intracellular calcium allows for the tightly regulated physiological activation of these proteins, which is crucial to a wide variety of cellular processes, such as fertilization, proliferation, development, learning, and memory. Deregulation of calpain and calcineurin has been implicated in the pathogenesis of several disorders, including hypertension, heart disease, diabetes, cerebral ischemia, and Alzheimer's disease. Recent studies have demonstrated an interplay between calpain and calcineurin, in which calpain can directly regulate calcineurin activity through proteolysis in glutamate-stimulated neurons in culture and in vivo. The calpain-mediated proteolytic cleavage of calcineurin increases phosphatase activity, which promotes caspase-mediated neuronal cell death. Thus, the activation of the calpain-calcineurin pathway could contribute to calcium-dependent disorders, especially those associated with Alzheimer's disease and myocardial hypertrophy. Here, we focus briefly on recent advances in revealing the structural and functional properties of these 2 calcium-activated proteins, as well as on the interplay between the 2, in an effort to understand how calpain-calcineurin signaling may relate to the pathogenesis of calcium- dependent disorders.
Topics: Alzheimer Disease; Apoptosis; Calcineurin; Calcium; Calpain; Cell Death; Humans; Models, Biological; Protein Structure, Tertiary; Signal Transduction
PubMed: 17593948
DOI: 10.18926/AMO/32905 -
Genome Biology 2007The calpain family is named for the calcium dependence of the papain-like, thiol protease activity of the well-studied ubiquitous vertebrate enzymes calpain-1... (Review)
Review
The calpain family is named for the calcium dependence of the papain-like, thiol protease activity of the well-studied ubiquitous vertebrate enzymes calpain-1 (mu-calpain) and calpain-2 (m-calpain). Proteins showing sequence relatedness to the catalytic core domains of these enzymes are included in this ancient and diverse eukaryotic protein family. Calpains are examples of highly modular organization, with several varieties of amino-terminal or carboxy-terminal modules flanking a conserved core. Acquisition of the penta-EF-hand module involved in calcium binding (and the formation of heterodimers for some calpains) seems to be a relatively late event in calpain evolution. Several alternative mechanisms for binding calcium and associating with membranes/phospholipids are found throughout the family. The gene family is expanded in mammals, trypanosomes and ciliates, with up to 26 members in Tetrahymena, for example; in striking contrast to this, only a single calpain gene is present in many other protozoa and in plants. The many isoforms of calpain and their multiple splice variants complicate the discussion and analysis of the family, and challenge researchers to ascertain the relationships between calpain gene sequences, protein isoforms and their distinct or overlapping functions. In mammals and plants it is clear that a calpain plays an essential role in development. There is increasing evidence that ubiquitous calpains participate in a variety of signal transduction pathways and function in important cellular processes of life and death. In contrast to relatively promiscuous degradative proteases, calpains cleave only a restricted set of protein substrates and use complex substrate-recognition mechanisms, involving primary and secondary structural features of target proteins. The detailed physiological significance of both proteolytically active calpains and those lacking key catalytic residues requires further study.
Topics: Animals; Calpain; Models, Molecular; Phylogeny
PubMed: 17608959
DOI: 10.1186/gb-2007-8-6-218 -
Scientific Reports Aug 2022Calpains are cysteine proteases involved in many cellular processes. They are an ancient and large superfamily of enzymes responsible for the cleavage and irreversible...
Calpains are cysteine proteases involved in many cellular processes. They are an ancient and large superfamily of enzymes responsible for the cleavage and irreversible modification of a large variety of substrates. They have been intensively studied in humans and other mammals, but information about calpains in bacteria is scarce. Calpains have not been found among Archaea to date. In this study, we have investigated the presence of calpains in selected cyanobacterial species using in silico analyses. We show that calpains defined by possessing CysPC core domain are present in cyanobacterial genera Anabaena, Aphanizomenon, Calothrix, Chamaesiphon, Fischerella, Microcystis, Scytonema and Trichormus. Based on in silico protein interaction analysis, we have predicted putative interaction partners for identified cyanobacterial calpains. The phylogenetic analysis including cyanobacterial, other bacterial and eukaryotic calpains divided bacterial and eukaryotic calpains into two separate monophyletic clusters. We propose two possible evolutionary scenarios to explain this tree topology: (1) the eukaryotic ancestor or an archaeal ancestor of eukaryotes obtained calpain gene from an unknown bacterial donor, or alternatively (2) calpain gene had been already present in the last common universal ancestor and subsequently lost by the ancestor of Archaea, but retained by the ancestor of Bacteria and by the ancestor of Eukarya. Both scenarios would require multiple independent losses of calpain genes in various bacteria and eukaryotes.
Topics: Animals; Archaea; Calpain; Cyanobacteria; Eukaryota; Humans; Phylogeny
PubMed: 35974045
DOI: 10.1038/s41598-022-18228-2 -
Proceedings of the Japan Academy.... 2011Calpain is an intracellular Ca2+-dependent cysteine protease (EC 3.4.22.17; Clan CA, family C02) discovered in 1964. It was also called CANP (Ca2+-activated neutral... (Review)
Review
Calpain is an intracellular Ca2+-dependent cysteine protease (EC 3.4.22.17; Clan CA, family C02) discovered in 1964. It was also called CANP (Ca2+-activated neutral protease) as well as CASF, CDP, KAF, etc. until 1990. Calpains are found in almost all eukaryotes and a few bacteria, but not in archaebacteria. Calpains have a limited proteolytic activity, and function to transform or modulate their substrates' structures and activities; they are therefore called, "modulator proteases." In the human genome, 15 genes--CAPN1, CAPN2, etc.--encode a calpain-like protease domain. Their products are calpain homologs with divergent structures and various combinations of functional domains, including Ca2+-binding and microtubule-interaction domains. Genetic studies have linked calpain deficiencies to a variety of defects in many different organisms, including lethality, muscular dystrophies, gastropathy, and diabetes. This review of the study of calpains focuses especially on recent findings about their structure-function relationships. These discoveries have been greatly aided by the development of 3D structural studies and genetic models.
Topics: Amino Acid Sequence; Animals; Calpain; Disease; Enzyme Activation; Humans; Molecular Sequence Data; Organ Specificity; Protein Structure, Tertiary
PubMed: 21670566
DOI: 10.2183/pjab.87.287 -
International Journal of Molecular... Nov 2020As a member of the calpain protein family, calpain6 (CAPN6) is highly expressed mainly in the placenta and embryos. It plays a number of important roles in cellular... (Review)
Review
As a member of the calpain protein family, calpain6 (CAPN6) is highly expressed mainly in the placenta and embryos. It plays a number of important roles in cellular processes, such as the stabilization of microtubules, the maintenance of cell stability, the control of cell movement and the inhibition of apoptosis. In recent years, various studies have found that CAPN6 is one of the contributing factors associated with the tumorigenesis of uterine tumors and osteosarcoma, and that CAPN6 participates in the development of tumors by promoting cell proliferation and angiogenesis, and by inhibiting apoptosis, which is mainly regulated by the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) pathway. Due to its abnormal cellular expression, CAPN6 has also been found to be associated with a number of diseases, such as white matter damage and muscular dystrophy. Therefore, CAPN6 may be a novel therapeutic target for these diseases. In the present review, the role of CAPN6 in disease and its possible use as a target in various therapies are discussed.
Topics: Animals; Calpain; Disease; Humans; Models, Biological; Molecular Targeted Therapy; Signal Transduction
PubMed: 33000175
DOI: 10.3892/ijmm.2020.4734 -
Bioscience Reports Apr 2021Calpain belongs to the calcium-dependent non-lysosomal cysteine protease. Calpain-1 (C1) and calpain-2 (C2) expression are ubiquitous in mammals and an important...
Calpain belongs to the calcium-dependent non-lysosomal cysteine protease. Calpain-1 (C1) and calpain-2 (C2) expression are ubiquitous in mammals and an important mediator of the action of calcium. Specific substrate cleavage by C1 and C2 is critical for several calcium-dependent cellular pathways including neuronal function, muscle contraction, signal transduction, cell differentiation, proliferation, and apoptosis. Research suggests that C1 and C2 perform similar functions due to their structurally highly similar isoforms. Increasing evidence suggests that C1 and C2 carry out their specific function in vivo. A recent paper published by Shinkai-Ouchi et al. (Bioscience Reports (2020) 40, DOI: 10.1042/BSR20200552) elucidated the mechanism to differentiate the function of each calpain with respect to the efficiency and longevity for proteolysis after activation. Further, the study represented that C1 and C2 do not synergistically perform their work in vitro. On the other hand, the activity of C1 is reduced in presence of C2. This insight establishes the platform for future studies to examine how C2 regulates the C1 for substrate proteolysis.
Topics: Animals; Apoptosis; Calcium; Calpain; Proteolysis; Signal Transduction
PubMed: 33749774
DOI: 10.1042/BSR20203690 -
Biochimica Et Biophysica Acta.... Aug 2023Neovascular inflammatory vitreoretinopathy (NIV) is a rare eye disease that ultimately leads to complete blindness and is caused by mutations in the gene encoding...
Neovascular inflammatory vitreoretinopathy (NIV) is a rare eye disease that ultimately leads to complete blindness and is caused by mutations in the gene encoding calpain-5 (CAPN5), with six pathogenic mutations identified. In transfected SH-SY5Y cells, five of the mutations resulted in decreased membrane association, diminished S-acylation, and reduced calcium-induced autoproteolysis of CAPN5. CAPN5 proteolysis of the autoimmune regulator AIRE was impacted by several NIV mutations. R243, L244, K250 and the adjacent V249 are on β-strands in the protease core 2 domain. Conformational changes induced by Cabinding result in these β-strands forming a β-sheet and a hydrophobic pocket which docks W286 side chain away from the catalytic cleft, enabling calpain activation based on comparison with the Ca-bound CAPN1 protease core. The pathologic variants R243L, L244P, K250N, and R289W are predicted to disrupt the β-strands, β-sheet, and hydrophobic pocket, impairing calpain activation. The mechanism by which these variants impair membrane association is unclear. G376S impacts a conserved residue in the CBSW domain and is predicted to disrupt a loop containing acidic residues which may contribute to membrane binding. G267S did not impair membrane association and resulted in a slight but significant increase in autoproteolytic and proteolytic activity. However, G267S is also identified in individuals without NIV. Combined with the autosomal dominant pattern of NIV inheritance and evidence that CAPN5 may dimerize, the results are consistent with a dominant negative mechanism for the five pathogenic variants which resulted in impaired CAPN5 activity and membrane association and a gain-of-function for the G267S variant.
Topics: Humans; Calpain; Neuroblastoma; Vitreoretinopathy, Proliferative; Mutation
PubMed: 37207905
DOI: 10.1016/j.bbadis.2023.166747 -
The Biochemical Journal Dec 1997For a long time now, two ubiquitously expressed mammalian calpain isoenzymes have been used to explore the structure and function of calpain. Although these two... (Review)
Review
For a long time now, two ubiquitously expressed mammalian calpain isoenzymes have been used to explore the structure and function of calpain. Although these two calpains, mu- and m-calpains, still attract intensive interest because of their unique characteristics, various distinct homologues to the protease domain of mu- and m-calpains have been identified in a variety of organisms. Some of these 'novel' calpain homologues are involved in important biological functions. For example, p94 (also called calpain 3), a mammalian calpain homologue predominantly expressed in skeletal muscle, is genetically proved to be responsible for limb-girdle muscular dystrophy type 2A. Tra-3, a calpain homologue in nematodes, is involved in the sex determination cascade during early development. PalB, a key gene product involved in the alkaline adaptation of Aspergillus nidulans, is the first example of a calpain homologue present in fungi. These findings indicate various important functional roles for intracellular proteases belonging to the calpain superfamily.
Topics: Amino Acid Sequence; Animals; Apoptosis; Brain; Calcium; Calcium-Binding Proteins; Calpain; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Humans; Molecular Sequence Data; Sex Determination Processes
PubMed: 9396712
DOI: 10.1042/bj3280721 -
Advances in Experimental Medicine and... 2017The calcium-dependent cytosolic, neutral, thiol endopeptidases, calpains, perform limited cleavage of their substrates thereby irreversibly changing their functions....
The calcium-dependent cytosolic, neutral, thiol endopeptidases, calpains, perform limited cleavage of their substrates thereby irreversibly changing their functions. Calpains have been shown to be involved in several physiological processes such as cell motility, proliferation, cell cycle, signal transduction, and apoptosis. Overactivation of calpain or mutations in the calpain genes contribute to a number of pathological conditions including neurodegenerative disorders, rheumatoid arthritis, cancer, and lung diseases. High concentrations of reactive oxygen and nitrogen species (RONS) originated from cigarette smoke or released by numerous cell types such as activated inflammatory cells and other respiratory cells cause oxidative and nitrosative stress contributing to the pathogenesis of COPD. RONS and calpain play important roles in the development of airway and pulmonary vascular remodeling in COPD. Published data show that increased RONS production is associated with increased calpain activation and/or elevated calpain protein level, leading to epithelial or endothelial barrier dysfunction, neovascularization, lung inflammation, increased smooth muscle cell proliferation, and deposition of extracellular matrix protein. Further investigation of the redox-dependent calpain signaling may provide future targets for the prevention and treatment of COPD.
Topics: Animals; Calpain; Humans; Mutation; Oxidation-Reduction; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Reactive Nitrogen Species; Reactive Oxygen Species; Respiratory System; Signal Transduction; Vascular Remodeling
PubMed: 29047085
DOI: 10.1007/978-3-319-63245-2_9 -
Biochimica Et Biophysica Acta.... Oct 2020Muscle atrophy is an inevitable sequel of fasting, denervation, aging, exposure to microgravity, and many human diseases including, cancer, type-2 diabetes, and renal... (Review)
Review
Muscle atrophy is an inevitable sequel of fasting, denervation, aging, exposure to microgravity, and many human diseases including, cancer, type-2 diabetes, and renal failure. During atrophy the destruction of the muscle's fundamental contractile machinery, the myofibrils, is accelerated leading to a reduction in muscle mass, weakness, frailty, and physical disability. Recent findings indicate that atrophy can be a major cause of death in affected individuals, and inhibition of muscle wasting is likely to prolong survival. Major advances in our understanding of the mechanisms for myofibril breakdown in atrophy include the discovery of biological pathways and key components that play prominent roles. On fasting or denervation, degradation of myofibrillar proteins requires an initial dissociation of the desmin cytoskeleton, whose integrity is critical for myofibril stability. This loss of desmin filaments involves phosphorylation, ubiquitination, and subsequent depolymerization by calpain-1, and appears to reduce myofibrils integrity and facilitate their destruction. Consequently, depolymerization of desmin filament in atrophy seems to be an early key event for overall proteolysis. A focus of this review is to discuss these new insights and the specific role of calpain-1 in promoting desmin filaments loss, and to highlight important key questions that merit further study.
Topics: Animals; Calpain; Desmin; Humans; Muscular Atrophy; Myofibrils; Polymerization; Ubiquitination
PubMed: 32603758
DOI: 10.1016/j.bbamcr.2020.118788