Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.54 (calpain 3)
 430 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p94, a muscle-specific member of calpain family, is unique in that it undergoes rapid and exhaustive autolysis with a half-life of less than 1 h resulting in its disappearance from muscle. Recently, p94 was shown to be responsible for limb girdle muscular dystrophy type 2A. To elucidate the muscular proteolytic system mediated by p94 and to solve the mystery of its unusually rapid autolysis, we searched for p94-binding proteins by the two-hybrid system. Although calpain small subunit plays a crucial role for regulation of ubiquitous calpains, it did not associate with p94. After a screening of skeletal muscle library, connectin (or titin), a gigantic filamentous protein spanning the M- to Z-lines of muscle sarcomere, was found to bind to p94 through a p94-specific region, IS2. The connectin-insoluble fraction of washed myofibrils contained full-length intact p94, suggesting that connectin regulates p94 activity.
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PMID:Muscle-specific calpain, p94, responsible for limb girdle muscular dystrophy type 2A, associates with connectin through IS2, a p94-specific sequence. 853 79

Using the yeast two-hybrid system, we have recently reported that skeletal muscle-specific calpain, p94, binds specifically to connectin (or titin), a gigantic muscle elastic protein. Connectin has at least two binding sites for p94; one is at the N2-line region and the other is at the extreme C-terminus. In order to analyze the interaction between p94 and the C-terminus of connectin, we examined the C-terminal sequence of human skeletal muscle connectin. The sequence was essentially identical to that of heart muscle reported by Labeit and Kolmerer (1995, Science 270, 293-296), and the minimal binding site for p94 contained two IgC2 motifs and the intervening sequence called "M-is7." The exon encoding M-is7 is reported to be alternatively spliced depending on muscle tissues, resulting in the existence of both types of connectin with and without M-is7. However, the C-terminal region of connectin bound to p94 through M-is7. Our results suggest that the interaction between p94 and the C-terminus of skeletal muscle-type connectin is involved in tissue-specific myofibriogenesis.
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PMID:Muscle-specific calpain, p94, interacts with the extreme C-terminal region of connectin, a unique region flanked by two immunoglobulin C2 motifs. 918 18

p94 (calpain3), a muscle-specific member of the calpain family, has been shown to be responsible for limb-girdle muscular dystrophy type 2A (LGMD2A), a form of autosomal recessive and progressive neuromuscular disorder. To elucidate the molecular mechanism of LGMD2A, we constructed nine p94 missense point mutants found in LGMD2A and analyzed their p94 unique properties. All mutants completely or almost completely lose the proteolytic activity against a potential substrate, fodrin. However, some of the mutants still possess autolytic activity and/or connectin/titin binding ability, indicating these properties are not necessary for the LGMD2A phenotypes. These results provide strong evidence that LGMD2A results from the loss of proteolysis of substrates by p94, suggesting a novel molecular mechanism leading to muscular dystrophies.
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PMID:Functional defects of a muscle-specific calpain, p94, caused by mutations associated with limb-girdle muscular dystrophy type 2A. 964 72

Recent studies indicate that calpain, a cytosolic Ca2+-dependent protease, constitutes a large family comprising ubiquitous, tissue-specific, and atypical calpains. p94 is a homologue of the catalytic large subunit of calpain, expressed predominantly in skeletal muscle. Recently, p94 has been found to interact with connectin/titin, a muscle elastic protein, and its gene has been identified as being responsible for limb-girdle muscular dystrophy type 2A. The loss of function of a calpain species eventually leads to the activation of proteases including other calpain species responsible for muscle degradation. p94 does not form a complex with the small subunit of calpain (30K), but exists as a homodimer. This, together with other results, led us to consider a novel mechanism for the activation of calpain, a Ca2+-induced subunit rearrangement.
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PMID:Skeletal muscle-specific calpain, p49: structure and physiological function. 976 16

The skeletal muscle-specific calpain homologue, p94 (also called calpain 3), is essential for normal muscle function. A mutation of the p94 gene causes limb-girdle muscular dystrophy type 2A (LGMD2A), which is one type of autosomal recessive inherited disease characterized by progressive muscular degeneration. In myofibrils, p94 specifically binds to connectin/titin, and the activity of p94 is probably suppressed by this binding. Thus, we postulate that a signal transduction pathway exists, involving p94 and connectin/titin to modulate functions of skeletal muscle, and LGMD2A occurs when this signalling pathway is not properly regulated by p94. LGMD2A mutants of p94 also reveal significant information on the factors that relate structure to function in this molecule.
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PMID:Skeletal muscle-specific calpain, p94, and connectin/titin: their physiological functions and relationship to limb-girdle muscular dystrophy type 2A. 1098 85

Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetically determined disorders with a primary or predominant involvement of the pelvic or shoulder girdle musculature. The clinical course is characterized by great variability, ranging from severe forms with rapid onset and progression to very mild forms allowing affected people to have fairly normal life spans and activity levels. Sixteen loci have been so far identified, six autosomal dominant and ten autosomal recessive. Linkage analyses indicate that there is further genetic heterogeneity both for dominant as well as for recessive LGMD. The dominant forms (LGMD1) are generally milder and relatively rare, representing less than 10% of all LGMD. The autosomal recessive forms (LGMD2) are much more common, having a cumulative prevalence of 1:15,000 with a number of geographical differences. The product of ten autosomal recessive LGMD genes has so far been identified. They are: calpain-3 (LGMD2A), dysferlin (LGMD2B), alpha-sarcoglycan (LGMD2D), beta-sarcoglycan (LGMD2E), gamma-sarcoglycan (LGMD2C), delta-sarcoglycan (LGMD2F), telethonin (LGMD2G), TRIM32 (LGMD2H), fukutin-related protein (LGMD2I) and titin (LGMD2J). There are, however, at least 25% of families who can be excluded from any known locus. The present review is devoted to outline the present advancements in the molecular bases of autosomal recessive LGMD.
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PMID:Molecular bases of autosomal recessive limb-girdle muscular dystrophies. 1495 61

Limb girdle muscular dystrophies (LGMDs) are a genetically heterogeneous group of primary myopathies involving progressive weakness and wasting of the muscles in the hip and shoulder girdles, with distal spread to the bulbar or respiratory musculature in rare cases. Depending on the mode of genetic transmission, six autosomal dominant forms (LGMD1A-F, 10-25%) and ten autosomal recessive forms (LGMD2A-J, 75-90%) are currently known. The prevalence of LGMDs is 0.8/100,000. These conditions are caused by mutations in genes encoding for myotilin (5q31, LGMD1A), lamin A/C (1q11-q21.2, LGMD1B), caveolin-3 (3p25, LGMD1C), unknown proteins (7q, LGMD1D, 6q23, LGMD1E, 7q32.1-32.2., LGMD1F), calpain-3 (15q15.1-21.1, LGMD2A), dysferlin (2p13.3-13.1, LGMD2B), gamma-sarcoglycan (13q12, LGMD2C), alpha-sarcoglycan, also known as adhalin (17q12-q21.3, LGMD2D), beta-sarcoglycan (4q12, LGMD2E), delta-sarcoglycan (5q33-q34, LGMD2F), telethonin (17q11-q12, LGMD2G), E3-ubiquitin ligase (9q31-q34.1, LGMD2H), fukutin-related protein (19q13.3, LGMD2I), and titin (2q31, LGMD2J). Cardiac involvement has been described for LGMD1B-E, LGMD2C-G, and LGMD2I. The time of onset varies between early childhood and middle age. There is no male or female preponderance. Disease progression and life expectancy vary widely, even among different members of the same family. The diagnosis is based primarily on DNA analysis. The history, clinical neurological examinations, blood chemistry investigations, electromyography, and muscle biopsy also provide information that is helpful for the diagnosis. No causal therapy is currently available.
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PMID:[Limb girdle muscular dystrophies]. 1531 18

Calpains are intracellular Ca2+ -requiring 'modulator proteases', which modulate cellular functions by limited and specific proteolysis. p94/calpain3, a skeletal-muscle specific calpain, has been one of the representative calpain species which indicates physiological importance of calpain proteolytic system; a defect of proteolytic activity of p94 causes limb girdle muscular dystrophy type2A (LGMD2A, also called 'calpainopathy'). Immunohistochemical studies on myofibrils showed that p94 localizes at the Z- and N2-line regions of sarcomeres. It was also identified by the yeast two hybrid studies that p94 binds to the N2A and M-line regions of connectin. Furthermore, genetic studies indicate that p94 is indispensable for skeletal muscles, although its precise functions are still unclear. Interestingly, connectin provides sarcomere not only with elasticity but also with binding sites to various multi-functional proteins such as muscle ankyrin repeat proteins (MARPs), muscle RING finger proteins (MURFs), titin-capping protein (T-cap/telethonin), sarcomeric-alpha-actinin, p94 etc. Binding sites for these proteins are not randomly placed along connectin but rather accumulated in the Z-, N2-, and/or M-line regions, indicating the existence of 'signal complexes' unique to each regions. The concept of these complexes are strongly supported by the facts that mutations of connectin or its binding proteins in these regions severely perturb muscle functions, as in the case of LGMD2A caused by mutations in the p94 gene. Therefore, it is hypothesized that the 'signal complexes' in the Z-, N2-, and M-lines modulate muscle cell homeostasis by transducing signals of external stimulations/stresses to trigger appropriate response at various different cellular events such as protein modification and gene expressions. In this article, we performed detailed immunohistochemical analyses of p94 on isolated single myofibers. Together with recent findings about p94, it is suggested that sarcomeric localization of p94, especially its M-line localization, is affected by the combination of cellular contexts such as contractile status of myofibrils, fiber type compositions, sarcomeric maturation, and the composition of the 'signal complexes' in each region.
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PMID:Possible functions of p94 in connectin-mediated signaling pathways in skeletal muscle cells. 1645 64

p94/calpain 3 is a skeletal muscle-specific member of the Ca(2+)-regulated cytosolic cysteine protease family, the calpains. Defective p94 protease activity originating from gene mutations causes a muscular dystrophy called calpainopathy, indicating the indispensability of p94 for muscle survival. Because of the existence of the p94-specific regions IS1 and IS2, p94 undergoes very rapid and exhaustive autolysis. To elucidate the physiological relevance of this unique activity, the autolytic profiles of p94 and the effect of the p94 binding protein, connectin/titin, on this process were investigated. In vitro analysis of p94 autolysis showed that autolysis in IS1 proceeds without immediate disassembly into fragments and that the newly identified cryptic autolytic site in IS2 is critical for disassembling autolyzed fragments. As a genetic system to assay p94 autolysis semiquantitatively, p94 was expressed in yeast as a hybrid protein between the DNA binding and activation domains of the yeast transcriptional activator Gal4. Transcriptional activation by the Gal4-p94:WT hybrid protein is precluded by p94 autolysis. Complete or partial loss of autolytic activity by C129S active site mutation, limb girdle muscular dystrophy type 2A pathogenic missense mutations, or PCR-based random mutagenesis could be detected by semiquantitative restoration of Gal4-dependent beta-galactosidase gene expression. Using this system, the N2A connectin fragment that binds to p94 was shown to suppress p94 autolytic disassembly. The proximity of the IS2 autolytic and connectin-binding sites in p94 suggested that N2A connectin suppresses IS2 autolysis. These data indicate the importance of p94-connectin interaction in the control of p94 functions by regulating autolytic decay of p94.
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PMID:Suppressed disassembly of autolyzing p94/CAPN3 by N2A connectin/titin in a genetic reporter system. 1662 76

p94/calpain 3 is a Ca(2+)-binding intracellular protease predominantly expressed in skeletal muscles. p94 binds to the N2A and M-line regions of connectin/titin and localizes in the Z-bands. Genetic evidence showing that compromised p94 proteolytic activity leads to muscular dystrophy (limb-girdle muscular dystrophy type 2A) indicates the importance of p94 function in myofibrils. Here we show that a series of p94 splice variants is expressed immediately after muscle differentiation and differentially change localization during myofibrillogenesis. We found that the endogenous N-terminal (but not C-terminal) domain of p94 was not only localized in the Z-bands but also directly bound to sarcomeric alpha-actinin. These data suggest the incorporation of proteolytic N-terminal fragments of p94 into the Z-bands. In myofibrils localization of exogenously expressed p94 shifted from the M-line to N2A as the sarcomere lengthens beyond approximately 2.6 and 2.8 microm for wild-type and proteaseinactive p94, respectively. These data demonstrate for the first time that p94 proteolytic activity is involved in responses to muscle conditions, which may explain why p94 inactivation causes limb-girdle muscular dystrophy.
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PMID:Myogenic stage, sarcomere length, and protease activity modulate localization of muscle-specific calpain. 1737 79


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