Structural modifications associated with the change in Ca<sup>2+</sup> sensitivity on activation of m‐calpain

Brown, Nicholas R.; Crawford, Catherine

doi:10.1016/0014-5793(93)81112-d

Cited by 59 publications

(41 citation statements)

References 21 publications

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“…However, there are amino acid preferences at positions surrounding calpain cleavage sites, with amino acids designated as P 4 -P 1 2P 1 Ј-P 7 Ј (32). There has been proposed a P 2 -P 1 rule, which states that the preferred residues for calpain are Leu and Val at position P 2 and Arg or Lys at P 1 (4,33,34). Pro dominates the region flanking the P 2 -P 1 Ј segment, particularly at P 3 Ј (35).…”

Section: Discussionmentioning

confidence: 99%

“…An important role is emerging for calpains in regulating inflammation and immune responses, although specific mechanisms by which this occurs have not been clearly defined (1-3). There are two major isoforms of this enzyme, -calpain (or calpain I) and m-calpain (or calpain II), which require micromolar and millimolar Ca 2ϩ concentrations for activity, respectively (4). These enzymes are comprised of an 80 kDa catalytic subunit and a 30 kDa regulatory subunit.…”

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confidence: 99%

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Selenoprotein K Is a Novel Target of m-Calpain, and Cleavage Is Regulated by Toll-like Receptor-induced Calpastatin in Macrophages

Huang

Hoffmann

Norton

et al. 2011

Journal of Biological Chemistry

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Background: Selenoprotein K is important for calcium-dependent activation of immune cells. Results: Selenoprotein K is cleaved by m-calpain in resting macrophages, but Toll-like receptor activation induces calpastatin generating full-length, functional selenoprotein K. Conclusion: Proteolytic modulation of selenoprotein K is important for macrophage activation. Significance: New roles are defined for the calpain/calpastatin system and selenoprotein K during macrophage activation and inflammation.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Selenoprotein K Is a Novel Target of m-Calpain, and Cleavage Is Regulated by Toll-like Receptor-induced Calpastatin in Macrophages

Huang

Hoffmann

Norton

et al. 2011

Journal of Biological Chemistry

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“…Although autolysis occurs rapidly, it involves several sequential steps: 1) for the 80-kDa subunit of -calpain, the NH 2 -terminal 14 amino acids are removed first to produce a 78-kDa intermediate product followed by removal of an additional 12 amino acids to produce the 76-kDa autolytic fragment (504; molecular weights as estimated with SDS-PAGE); 2) for the 80-kDa subunit of m-calpain, the NH 2 -terminal 9 amino acids are removed first followed by removal of an additional 10 amino acids to produce the 78-kDa autolytic fragment (45); and 3) for the 28-kDa subunit, the NH 2 -terminal 26 amino acids are removed to produce a 26-to 27-kDa fragment, an additional 37 amino acids (to Gly-64) are then removed to produce a 22-to 23-kDa fragment, and finally 28 more amino acids (to Ala-92) are removed to produce the 18-kDa (20.5 kDa) autolytic fragment (272). The 28-kDa subunit of m-calpain is autolyzed more rapidly than the 80-kDa subunit (45,73), whereas autolysis of the 80-kDa subunit in the -calpain molecule seems to proceed as rapidly as or even more rapidly than autolysis of the 28-kDa subunit in this molecule (45,68,504).…”

Section: Autolysis and The Proenzyme Questionmentioning

confidence: 99%

The Calpain System

Goll

Thompson

et al. 2003

Physiological Reviews

2,553

2,801

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Goll, Darrel E., Valery F. Thompson, Hongqi Li, Wei Wei, and Jinyang Cong. The Calpain System. Physiol Rev 83: 731–801, 2003; 10.1152/physrev.00029.2002.—The calpain system originally comprised three molecules: two Ca2+-dependent proteases, μ-calpain and m-calpain, and a third polypeptide, calpastatin, whose only known function is to inhibit the two calpains. Both μ- and m-calpain are heterodimers containing an identical 28-kDa subunit and an 80-kDa subunit that shares 55–65% sequence homology between the two proteases. The crystallographic structure of m-calpain reveals six “domains” in the 80-kDa subunit: 1) a 19-amino acid NH2-terminal sequence; 2) and 3) two domains that constitute the active site, IIa and IIb; 4) domain III; 5) an 18-amino acid extended sequence linking domain III to domain IV; and 6) domain IV, which resembles the penta EF-hand family of polypeptides. The single calpastatin gene can produce eight or more calpastatin polypeptides ranging from 17 to 85 kDa by use of different promoters and alternative splicing events. The physiological significance of these different calpastatins is unclear, although all bind to three different places on the calpain molecule; binding to at least two of the sites is Ca2+ dependent. Since 1989, cDNA cloning has identified 12 additional mRNAs in mammals that encode polypeptides homologous to domains IIa and IIb of the 80-kDa subunit of μ- and m-calpain, and calpain-like mRNAs have been identified in other organisms. The molecules encoded by these mRNAs have not been isolated, so little is known about their properties. How calpain activity is regulated in cells is still unclear, but the calpains ostensibly participate in a variety of cellular processes including remodeling of cytoskeletal/membrane attachments, different signal transduction pathways, and apoptosis. Deregulated calpain activity following loss of Ca2+ homeostasis results in tissue damage in response to events such as myocardial infarcts, stroke, and brain trauma.

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“…Overall, high Se status in macrophages may perturb redox tone either through antioxidant selenoproteins or through small-molecular-weight selenocompounds, either of which may inhibit NFjB signaling during activation. (30). These enzymes are comprised of an 80 kDa catalytic subunit and a 30 kDa regulatory subunit.…”

Section: The Effects Of Se Intake On Camentioning

confidence: 99%

The Role of Selenium in Inflammation and Immunity: From Molecular Mechanisms to Therapeutic Opportunities

Huang

Rose

Hoffmann

2012

Antioxidants & Redox Signaling

684

496

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Dietary selenium (]Se), mainly through its incorporation into selenoproteins, plays an important role in inflammation and immunity. Adequate levels of Se are important for initiating immunity, but they are also involved in regulating excessive immune responses and chronic inflammation. Evidence has emerged regarding roles for individual selenoproteins in regulating inflammation and immunity, and this has provided important insight into mechanisms by which Se influences these processes. Se deficiency has long been recognized to negatively impact immune cells during activation, differentiation, and proliferation. This is related to increased oxidative stress, but additional functions such as protein folding and calcium flux may also be impaired in immune cells under Se deficient conditions. Supplementing diets with above-adequate levels of Se can also impinge on immune cell function, with some types of inflammation and immunity particularly affected and sexually dimorphic effects of Se levels in some cases. In this comprehensivearticle, the roles of Se and individual selenoproteins in regulating immune cell signaling and function are discussed. Particular emphasis is given to how Se and selenoproteins are linked to redox signaling, oxidative burst, calcium flux, and the subsequent effector functions of immune cells. Data obtained from cell culture and animal models are reviewed and compared with those involving human physiology and pathophysiology, including the effects of Se levels on inflammatory or immune-related diseases including anti-viral immunity, autoimmunity, sepsis, allergic asthma, and chronic inflammatory disorders. Finally, the benefits and potential adverse effects of intervention with Se supplementation for various inflammatory or immune disorders are discussed. Antioxid. Redox Signal. 16, 705-743.

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Structural modifications associated with the change in Ca²⁺ sensitivity on activation of m‐calpain

Cited by 59 publications

References 21 publications

Selenoprotein K Is a Novel Target of m-Calpain, and Cleavage Is Regulated by Toll-like Receptor-induced Calpastatin in Macrophages

Selenoprotein K Is a Novel Target of m-Calpain, and Cleavage Is Regulated by Toll-like Receptor-induced Calpastatin in Macrophages

The Calpain System

The Role of Selenium in Inflammation and Immunity: From Molecular Mechanisms to Therapeutic Opportunities

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Structural modifications associated with the change in Ca2+ sensitivity on activation of m‐calpain

Cited by 59 publications

References 21 publications

Selenoprotein K Is a Novel Target of m-Calpain, and Cleavage Is Regulated by Toll-like Receptor-induced Calpastatin in Macrophages

Selenoprotein K Is a Novel Target of m-Calpain, and Cleavage Is Regulated by Toll-like Receptor-induced Calpastatin in Macrophages

The Calpain System

The Role of Selenium in Inflammation and Immunity: From Molecular Mechanisms to Therapeutic Opportunities

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Product

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Structural modifications associated with the change in Ca²⁺ sensitivity on activation of m‐calpain