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

Only the 80-kD catalytic subunit of smooth muscle calpain II shows a change in intrinsic fluorescence on binding calcium, but both the 80-kD and 30-kD subunits show fluorescence changes in bound toluidinyl-naphthalenesulphonate as a result of calcium binding. Both subunits also show changes in intrinsic fluorescence in the presence of calmidazolium and felodipine. These studies indicate that both subunits have binding sites for calcium and the calmodulin antagonists, which are probably located in the calmodulin-like domain of each subunit.
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PMID:Effects of calcium and calmodulin antagonists on calpain II subunit conformations. 209 9

Calpains are calcium-dependent intracellular nonlysosomal proteases that are believed to participate in signal transduction. In vertebrates, five different calpains have so far been identified, of which three, mu-, m-, and mu/m-calpain, are ubiquitously expressed while the other two, nCL-1 (p94) and nCL-2, exhibit a restricted tissue distribution. We have identified two new vertebrate calpain genes, Capn5 and Capn6. The human and mouse amino acid sequences of these new calpains are the most divergent of the vertebrate calpains identified. They possess most of the residues conserved in calpain family members but the C-terminal region lacks any homology to the calmodulin-like domain of other vertebrate calpains. They both exhibit significant homology over the entire coding region to the protein encoded by the gene tra-3, involved in nematode sex determination, and Capn5 may represent its vertebrate orthologue. The predicted Capn6 protein lacks critical active site residues and may not be proteolytically active. Both genes are differentially expressed in human tissues with highest RNA levels for Capn5 occurring in the testis, liver, trachea, colon, and kidney, while Capn6 is highly expressed only in the placenta sample of the 50 tissues examined. Phylogenetic analysis suggests that the vertebrate calpains arose through a series of gene duplication events that began before the initial divergence of the vertebrate and invertebrate lineages. The discovery of these two new calpains highlights a hitherto unknown complexity of the calpain family with subclasses perhaps possessing different modes of regulation.
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PMID:A new subfamily of vertebrate calpains lacking a calmodulin-like domain: implications for calpain regulation and evolution. 933 74

Mutations in the non-lysosomal, cysteine protease calpain 3 (CAPN3) result in the disease limb girdle muscular dystrophy type 2A (LGMD2A). CAPN3 is localized to several subcellular compartments, including triads, where it plays a structural, rather than a proteolytic, role. In the absence of CAPN3, several triad components are reduced, including the major Ca(2+) release channel, ryanodine receptor (RyR). Furthermore, Ca(2+) release upon excitation is impaired in the absence of CAPN3. In the present study, we show that Ca-calmodulin protein kinase II (CaMKII) signaling is compromised in CAPN3 knockout (C3KO) mice. The CaMK pathway has been previously implicated in promoting the slow skeletal muscle phenotype. As expected, the decrease in CaMKII signaling that was observed in the absence of CAPN3 is associated with a reduction in the slow versus fast muscle fiber phenotype. We show that muscles of WT mice subjected to exercise training activate the CaMKII signaling pathway and increase expression of the slow form of myosin; however, muscles of C3KO mice do not exhibit these adaptive changes to exercise. These data strongly suggest that skeletal muscle's adaptive response to functional demand is compromised in the absence of CAPN3. In agreement with our mouse studies, RyR levels were also decreased in biopsies from LGMD2A patients. Moreover, we observed a preferential pathological involvement of slow fibers in LGMD2A biopsies. Thus, impaired CaMKII signaling and, as a result, a weakened muscle adaptation response identify a novel mechanism that may underlie LGMD2A and suggest a pharmacological target that should be explored for therapy.
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PMID:Impaired calcium calmodulin kinase signaling and muscle adaptation response in the absence of calpain 3. 2250 82

Calpains are broadly distributed, calcium-dependent enzymes that induce limited proteolysis in a wide range of substrates. Mutations in the gene encoding the muscle-specific family member calpain 3 (CAPN3) underlie limb-girdle muscular dystrophy 2A. We have shown previously that CAPN3 knockout muscles exhibit attenuated calcium release, reduced calmodulin kinase (CaMKII) signaling, and impaired muscle adaptation to exercise. However, neither the precise role of CAPN3 in these processes nor the mechanisms of CAPN3 activation in vivo have been fully elucidated. In this study, we identify calmodulin (CaM), a known transducer of the calcium signal, as the first positive regulator of CAPN3 autolytic activity. CaM was shown to bind CAPN3 at two sites located in the C2L domain. Biochemical studies using muscle extracts from transgenic mice overexpressing CAPN3 or its inactive mutant revealed that CaM binding enhanced CAPN3 autolytic activation. Furthermore, CaM facilitated CAPN3-mediated cleavage of its in vivo substrate titin in tissue extracts. Therefore, these studies reveal a novel interaction between CAPN3 and CaM and identify CaM as the first positive regulator of CAPN3 activity.
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PMID:Autolytic activation of calpain 3 proteinase is facilitated by calmodulin protein. 2538 88