Calpain-3 not only proteolyzes calpain-1 and -2 but also is a substrate for calpain-1 and -2.

Calpain is an intracellular cysteine protease that cleaves its specific substrates in a limited region to modulate cellular function. Calpain-1 (C1) and calpain-2 (C2) are ubiquitously expressed in mammalian cells, but calpain-3 (C3) is a skeletal muscle-specific type. In the course of calpain activation, the N-terminal regions of all three isoforms are clipped off in an intramolecular or intermolecular fashion.

The UFM1 system regulates ER-phagy through the ufmylation of CYB5R3.

Protein modification by ubiquitin-like proteins (UBLs) amplifies limited genome information and regulates diverse cellular processes, including translation, autophagy and antiviral pathways. Ubiquitin-fold modifier 1 (UFM1) is a UBL covalently conjugated with intracellular proteins through ufmylation, a reaction analogous to ubiquitylation. Ufmylation is involved in processes such as endoplasmic reticulum (ER)-associated protein degradation, ribosome-associated protein quality control at the ER and ER-phagy.

Cryptic splicing events result in unexpected protein products from calpain-10 (CAPN10) cDNA.

Calpain-10 (CAPN10) belongs to the calpain superfamily. Genetic polymorphisms of the CAPN10 gene are associated with susceptibility to develop type 2 diabetes mellitus. Although the role of CAPN10 in the pathophysiology of diabetes has been extensively investigated, its biochemical properties are largely unknown.

Calpain-2 participates in the process of calpain-1 inactivation.

Calpain-1 and calpain-2 are highly structurally similar isoforms of calpain. The calpains, a family of intracellular cysteine proteases, cleave their substrates at specific sites, thus modifying their properties such as function or activity. These isoforms have long been considered to function in a redundant or complementary manner, as they are both ubiquitously expressed and activated in a Ca2+- dependent manner.

Developing fluorescence sensor probe to capture activated muscle-specific calpain-3 (CAPN3) in living muscle cells.

Calpain-3 (CAPN3) is a muscle-specific type of calpain whose protease activity is triggered by Ca Here, we developed CAPN3 sensor probes (SPs) to detect activated-CAPN3 using a fluorescence/Förster resonance energy transfer (FRET) technique. In our SPs, partial amino acid sequence of calpastatin, endogenous CAPN inhibitor but CAPN3 substrate, is inserted between two different fluorescence proteins that cause FRET. Biochemical and spectral studies revealed that CAPN3 cleaved SPs and changed emission wavelengths of SPs.

A muscle-specific calpain, CAPN3, forms a homotrimer.

Calpain-3 (CAPN3), a 94-kDa member of the calpain protease family, is abundant in skeletal muscle. Mutations in the CAPN3 gene cause limb girdle muscular dystrophy type 2A, indicating that CAPN3 plays important roles in muscle physiology. CAPN3 has several unique features.

Calpain research for drug discovery: challenges and potential.

Calpains are a family of proteases that were scientifically recognized earlier than proteasomes and caspases, but remain enigmatic. However, they are known to participate in a multitude of physiological and pathological processes, performing 'limited proteolysis' whereby they do not destroy but rather modulate the functions of their substrates. Calpains are therefore referred to as 'modulator proteases'.

Amino acid sequence alignment of vertebrate CAPN3/calpain-3/p94.

CAPN3 is a calpain superfamily member that is predominantly expressed in skeletal muscle. So far, clear CAPN3 orthologs were found only in vertebrates. CAPN3 is a unique protease in that it undergoes extremely rapid and exhaustive autolysis and that autolyzed fragments spontaneously associate each other to reconstitute the proteolytic activity.

Predictions of Cleavability of Calpain Proteolysis by Quantitative Structure-Activity Relationship Analysis Using Newly Determined Cleavage Sites and Catalytic Efficiencies of an Oligopeptide Array.

Calpains are intracellular Ca(2+)-regulated cysteine proteases that are essential for various cellular functions. Mammalian conventional calpains (calpain-1 and calpain-2) modulate the structure and function of their substrates by limited proteolysis. Thus, it is critically important to determine the site(s) in proteins at which calpains cleave.

An eccentric calpain, CAPN3/p94/calpain-3.

Calpains are Ca(2+)-regulated proteolytic enzymes that are involved in a variety of biological phenomena. Calpains process substrates by limited proteolysis to modulate various protein functions in the cell, and are thus called "modulator proteases." CAPN3, previously called p94 or calpain-3, has unique features that are not found in any of the other 14 human calpains, or even in other proteases.

The N- and C-terminal autolytic fragments of CAPN3/p94/calpain-3 restore proteolytic activity by intermolecular complementation.

CAPN3/p94/calpain-3, a calpain protease family member predominantly expressed in skeletal muscle, possesses unusually rapid and exhaustive autolytic activity. Mutations in the human CAPN3 gene impairing its protease functions cause limb-girdle muscular dystrophy type 2A (LGMD2A); yet, the connection between CAPN3's autolytic activity and the enzyme's function in vivo remain unclear. Here, we demonstrated that CAPN3 protease activity was reconstituted by intermolecular complementation (iMOC) between its two autolytic fragments.

Muscle-specific calpain-3 is phosphorylated in its unique insertion region for enrichment in a myofibril fraction.

CAPN3 (also called p94/calpain-3) is a skeletal muscle-specific calpain, an intracellular cysteine protease. Loss of CAPN3 protease activity and/or structural functions cause limb-girdle muscular dystrophy type 2A (LGMD2A). However, the precise mechanism of action of CAPN3 in skeletal muscles in vivo remains largely elusive.

Involvement of calpain-7 in epidermal growth factor receptor degradation via the endosomal sorting pathway.

Unlabelled: Calpain-7 (CAPN7) is a unique intracellular cysteine protease that has a tandem repeat of microtubule interacting and trafficking (MIT) domains and lacks a penta-EF-hand domain. Although the MIT domains of CAPN7 were previously shown to interact with a subset of endosomal sorting complex required for transport (ESCRT)-III and ESCRT-III-related proteins, including charged multivesicular body protein 1 and increased sodium tolerance (IST)1, knowledge of the involvement of the protease in membrane trafficking has been limited. In the present study, compared with control cells, we found that epidermal growth factor receptor (EGFR) degradation was mildly delayed in CAPN7-knockdown HeLa cells and mouse embryonic fibroblast cells established from CAPN7 knockout (Capn7(-/-) ) mice.

Removal of immunoglobulin-like domains from titin's spring segment alters titin splicing in mouse skeletal muscle and causes myopathy.

Titin is a molecular spring that determines the passive stiffness of muscle cells. Changes in titin's stiffness occur in various myopathies, but whether these are a cause or an effect of the disease is unknown. We studied a novel mouse model in which titin's stiffness was slightly increased by deleting nine immunoglobulin (Ig)-like domains from titin's constitutively expressed proximal tandem Ig segment (IG KO).

Calpain-6 deficiency promotes skeletal muscle development and regeneration.

Calpains are Ca(2+)-dependent modulator Cys proteases that have a variety of functions in almost all eukaryotes. There are more than 10 well-conserved mammalian calpains, among which eutherian calpain-6 (CAPN6) is unique in that it has amino acid substitutions at the active-site Cys residue (to Lys in humans), strongly suggesting a loss of proteolytic activity. CAPN6 is expressed predominantly in embryonic muscles, placenta, and several cultured cell lines.

PLEIAD/SIMC1/C5orf25, a novel autolysis regulator for a skeletal-muscle-specific calpain, CAPN3, scaffolds a CAPN3 substrate, CTBP1.

CAPN3/p94/calpain-3 is a skeletal-muscle-specific member of the calpain protease family. Multiple muscle cell functions have been reported for CAPN3, and mutations in this protease cause limb-girdle muscular dystrophy type 2A. Little is known about the molecular mechanisms that allow CAPN3 to be so multifunctional.

Understanding the substrate specificity of conventional calpains.

Calpains are intracellular Ca(2+)-dependent Cys proteases that play important roles in a wide range of biological phenomena via the limited proteolysis of their substrates. Genetic defects in calpain genes cause lethality and/or functional deficits in many organisms, including humans. Despite their biological importance, the mechanisms underlying the action of calpains, particularly of their substrate specificities, remain largely unknown.

Regulation and physiological roles of the calpain system in muscular disorders.

Calpains, a family of Ca(2+)-dependent cytosolic cysteine proteases, can modulate their substrates' structure and function through limited proteolytic activity. In the human genome, there are 15 calpain genes. The most-studied calpains, referred to as conventional calpains, are ubiquitous.

Does the severity of the LGMD2A phenotype in compound heterozygotes depend on the combination of mutations?

Introduction: Limb-girdle muscular dystrophy type 2A (LGMD2A) is caused by a deficiency of calpain-3/p94. Although the symptoms in most LGMD2A patients are generally homogeneous, some variation in the severity and progression of the disease has been reported.

Methods: We describe 2 patients who carry the same combination of compound heterozygous mutations (pG222R/pR748Q) and whose symptoms are exceptionally benign compared to homozygotes with each missense mutation.

Calpains: an elaborate proteolytic system.

Calpain is an intracellular Ca(2+)-dependent cysteine protease (EC 3.4.22.

Calpain chronicle--an enzyme family under multidisciplinary characterization.

Calpain is an intracellular Ca2+-dependent cysteine protease (EC 3.4.22.

Impact of genetic insights into calpain biology.

Calpain has long been an enigmatic enzyme, although it is involved in a variety of biological phenomena. Recent progress in calpain genetics has highlighted numerous physiological contexts in which the functions of calpain are of great significance. This review focuses on recent findings in the field of calpain genetics and the importance of calpain function.

Calpain cleavage prediction using multiple kernel learning.

Calpain, an intracellular Ca²⁺-dependent cysteine protease, is known to play a role in a wide range of metabolic pathways through limited proteolysis of its substrates. However, only a limited number of these substrates are currently known, with the exact mechanism of substrate recognition and cleavage by calpain still largely unknown. While previous research has successfully applied standard machine-learning algorithms to accurately predict substrate cleavage by other similar types of proteases, their approach does not extend well to calpain, possibly due to its particular mode of proteolytic action and limited amount of experimental data.

Non-proteolytic functions of calpain-3 in sarcoplasmic reticulum in skeletal muscles.

Mutations in CAPN3/Capn3, which codes for skeletal muscle-specific calpain-3/p94 protease, are responsible for limb-girdle muscular dystrophy type 2A. Using "knock-in" (referred to as Capn3(CS/CS)) mice, in which the endogenous calpain-3 is replaced with a mutant calpain-3:C129S, which is a proteolytically inactive but structurally intact calpain-3, we demonstrated in our previous studies that loss of calpain-3 protease activity causes muscular dystrophy [Ojima, K. et al.