The tra-3 sex determination gene of Caenorhabditis elegans encodes a member of the calpain regulatory protease family.

Barnes, Thomas M.; Hodgkin, Jonathan

doi:10.1002/j.1460-2075.1996.tb00825.x

Cited by 103 publications

(85 citation statements)

References 71 publications

(64 reference statements)

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“…1). The importance of the physiological roles of calpains is reflected by the fact that particular defects in calpain functionality have effects in many different organisms, including lethality (e.g., disruption of mouse Capn2, which encodes the catalytic subunit of m-calpain) or a variety of deficiencies (e.g., mutations in human CAPN3, which encodes the muscle-specific calpain) including muscular dystrophies [133], lissencephaly [177], and tumorigenesis [79] in humans, embryonic lethality in mice [4,34,183], impaired neurogenesis in flies [30], lack of definitive sex determination in nematodes [9], defects in aleurone cell development in maize [90], and alkaline/osmotic stress susceptibility in fungi [32] and yeasts [44,58]. The following sections discuss several disease-related effects of calpains in terms of their animal models, and the divergent physiological roles of calpains are described mainly from the viewpoint of structure-function relationships.…”

Section: -Reviewreview Series: Frontiers Of Model Animals For Human Dmentioning

confidence: 99%

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

2010

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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.

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Section: -Reviewreview Series: Frontiers Of Model Animals For Human Dmentioning

confidence: 99%

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

2010

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“…Genetic evidence shows that many of these atypical calpains are, like conventional calpains, involved in signal transduction cascades, tissue differentiation, and sex determination. In Caenorhabditis elegans, the calpain-like protein TRA-3 is involved in a pathway leading to female worms (Barnes and Hodgkin 1996). TRA-3 lacks a typical domain IV.…”

Section: Introductionmentioning

confidence: 99%

Evolutionary Relationships and Protein Domain Architecture in an Expanded Calpain Superfamily in Kinetoplastid Parasites

2005

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Abstract. Employing whole-genome analysis we have characterized a large family of genes coding for calpain-related proteins in three kinetoplastid parasites. We have defined a total of 18 calpain-like sequences in Trypanosoma brucei, 27 in Leishmania major, and 24 in Trypanosoma cruzi. Sequence characterization revealed a well-conserved protease domain in most proteins, although residues critical for catalytic activity were frequently altered. Many of the proteins contain a novel N-terminal sequence motif unique to kinetoplastids. Furthermore, 24 of the sequences contain N-terminal fatty acid acylation motifs indicating association of these proteins with intracellular membranes. This extended family of proteins also includes a group of sequences that completely lack a protease domain but is specifically related to other kinetoplastid calpain-related proteins by a highly conserved N-terminal domain and by genomic organization. All sequences lack the C-terminal calmodulin-related calcium-binding domain typical of most mammalian calpains. Our analysis emphasizes the highly modular structure of calpains and calpain-like proteins, suggesting that they are involved in diverse cellular functions. The discovery of this surprisingly large family of calpain-like proteins in lower eukaryotes that combines novel and conserved sequence modules contributes to our understanding of the evolution of this abundant protein family.

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“…Mutations in the calpain genes of various other organisms, including yeasts, plants, nematodes, and Drosophila, result in significant phenotypes corresponding to defects in stress responses, sex determination, organogenesis, etc. (11)(12)(13)(14)(15). However, our understanding of the specific molecular mechanisms underlying calpain functions in vivo is far from complete.…”

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confidence: 99%

Stomach-specific Calpain, nCL-2, Localizes in Mucus Cells and Proteolyzes the β-Subunit of Coatomer Complex, β-COP

Hata

Koyama

Kawahara

et al. 2006

Journal of Biological Chemistry

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Calpain is a Ca2؉ -regulated cytosolic protease. Mammals have 14 calpain genes, half of which are predominantly expressed in specific organ(s); the rest are expressed ubiquitously. A defect in calpains causes lethality/pathogenicity, indicating their physiological indispensability. nCL-2/calpain-8a was identified as a stomach-specific calpain, whose physiological functions are unclear. To elucidate these, we characterized nCL-2 in detail. Unexpectedly, nCL-2 was localized strictly to the surface mucus cells in the gastric epithelium and the mucus-secreting goblet cells in the duodenum. Yeast twohybrid screening identified several nCL-2-intracting molecules. Of these, the ␤-subunit of coatomer complex (␤-COP) occurs in the stomach pit cells and is proteolyzed by nCL-2 in vitro. Furthermore, ␤-COP and nCL-2 co-expressed in COS7 cells co-localized in the Golgi, and Ca 2؉ -ionophore stimulation caused the proteolysis of ␤-COP near the linker region, resulting in the dissociation of ␤-COP from the Golgi. These results strongly suggest novel functions for nCL-2 that involve the membrane trafficking of mucus cells via interactions with coat protein.Calpain (EC 3.4.22.17) is an intracellular Ca 2ϩ -regulated cysteine protease, comprising a superfamily in most organisms, including some bacteria, budding yeasts, fungi, plants, and animals. Calpains proteolyze specific substrates at very limited sites to irreversibly modify/modulate their functions, structures, and activities, and are thus called "modulator proteases." Fourteen calpain genes have been identified in humans and mice and can be classified into two categories according to their expression, i.e. ubiquitous or tissue-specific (1-3). Ubiquitous -and m-calpains, two major calpains in mammals, form a heterodimer composed of a distinct 80-kDa catalytic large subunit (abbreviated to "CL" and "mCL," respectively) 2 and a common 30-kDa regulatory small subunit (30K). Calpain three-dimensional structures define four (I-IV) and two (V and VI) domains in the large and small subunits, respectively: the regulatory N-terminal domain (I), the protease domain (II), the C2-domain-like Ca 2ϩ /phospholipid-binding domain (III), the penta-EF-hand domains (IV and VI), and the Glyclustering domain (V) (4, 5). In the absence of Ca 2ϩ , the protease domain (II) is further divided into two subdomains, IIa and IIb, which form a single active domain upon binding to Ca 2ϩ (6, 7). Genetic studies in mammals and other organisms have clearly shown the physiological indispensability of the calpains. A gene knock-out mouse with a mutation in the gene for 30K, Capn4, exhibits embryonic lethality (8); mutations in the human gene for skeletal-muscle-specific p94/calpain 3, CAPN3, are responsible for limb-girdle muscular dystrophy type 2A (9); and a single nucleotide polymorphism in intron 3 of the human gene for calpain 10, CAPN10, is associated with type 2 diabetes (10). Mutations in the calpain genes of various other organisms, including yeasts, plants, nematodes, and Drosophila, result in sign...

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The tra-3 sex determination gene of Caenorhabditis elegans encodes a member of the calpain regulatory protease family.

Cited by 103 publications

References 71 publications

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

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

Evolutionary Relationships and Protein Domain Architecture in an Expanded Calpain Superfamily in Kinetoplastid Parasites

Stomach-specific Calpain, nCL-2, Localizes in Mucus Cells and Proteolyzes the β-Subunit of Coatomer Complex, β-COP

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