Modulation of the Calpain Autoproteolysis by Calpastatin and Phospholipids

Melloni, Edon; Michetti, M.; Salamino, Franca; Minafra, Roberto; Pontremoli, S.

doi:10.1006/bbrc.1996.1779

Cited by 86 publications

(86 citation statements)

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“…The binding of phospholipids also decreases the calcium requirement for calpains in vitro (Arthur and Crawford, 1996;Melloni et al, 1996;Saido et al, 1992;Suzuki et al, 1992;Tompa et al, 2001), but the in vivo relevance of this is unknown. Similarly, regulation of protein-protein interactions changes the calcium requirements of calpains (Melloni et al, 2000a;Melloni et al, 2000b;Melloni et al, 1998;Melloni et al, 2000c;Michetti et al, 1991;Salamino et al, 1993), but their roles in activation are not clear.…”

Section: Calpain Regulationmentioning

confidence: 99%

Regulating cell migration: calpains make the cut

Franco

Huttenlocher

2005

Journal of Cell Science

437

406

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The calpain family of proteases has been implicated in cellular processes such as apoptosis, proliferation and cell migration. Calpains are involved in several key aspects of migration, including: adhesion and spreading; detachment of the rear; integrin- and growth-factor-mediated signaling; and membrane protrusion. Our understanding of how calpains are activated and regulated during cell migration has increased as studies have identified roles for calcium and phospholipid binding, autolysis, phosphorylation and inhibition by calpastatin in the modulation of calpain activity. Knockout and knockdown approaches have also contributed significantly to our knowledge of calpain biology, particularly with respect to the specific functions of different calpain isoforms. The mechanisms by which calpain-mediated proteolysis of individual substrates contributes to cell motility have begun to be addressed, and these efforts have revealed roles for proteolysis of specific substrates in integrin activation, adhesion complex turnover and membrane protrusion dynamics. Understanding these mechanisms should provide avenues for novel therapeutic strategies to treat pathological processes such as tumor metastasis and chronic inflammatory disease.

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Section: Calpain Regulationmentioning

confidence: 99%

Regulating cell migration: calpains make the cut

Franco

Huttenlocher

2005

Journal of Cell Science

437

406

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“…This initial step in the activation of calpain is followed by the partial or complete autoproteolytic removal of the N-terminal segment, which includes the catalytic region. The two resulting, fully active, 78 kDa and 75 kDa protease forms can rapidly interact with calpastatin with high affinity [7].…”

Section: Introductionmentioning

confidence: 99%

“…In the first stage, induced by conformational transition, the primary effect is to prevent autoproteolytic conversion to the fully active, low-molecularmass forms. In the final stage, interaction with calpastatin results in the inhibition of the catalytic activity [7].…”

Section: Introductionmentioning

confidence: 99%

Changes in intracellular localization of calpastatin during calpain activation

Tullio

Passalacqua

Averna

et al. 1999

Biochemical Journal

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Localization of the two main components of the Ca2+-dependent proteolytic system has been investigated in human neuroblastoma LAN-5 cells. Using a monoclonal antibody which recognizes the N-terminal calpastatin domain, it has been shown that this inhibitory protein is almost completely confined in two granule-like structures not surrounded by membranes. Similar calpastatin distribution has been found in other human and in murine cell types, indicating that aggregation of calpastatin is a general property and not an exclusive characteristic of neuronal-like cells. The existence of such calpastatin aggregates is confirmed by the kinetics of calpastatin-activity release during rat liver homogenization, which does not correspond to the rate of appearance of cytosolic proteins or to the disruption of membrane-surrounded organelles. Calpastatin distribution is affected by the intracellular increase in free Ca2+, which results in calpastatin progressively becoming a soluble protein. However, calpain is distributed in the soluble cell fraction and, in activating conditions, partially accumulates on the plasma membrane. Similar behaviour has been observed in calpastatin localization in LAN-5 cells induced with retinoic acid, suggesting that the proteolytic system is activated during the differentiation process of these cells. The involvement of calpastatin in controlling calpain activity, rather than its activation process, and the utilization of changes in calpastatin localization as a marker of activation of the system is discussed.

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“…2, #9, and Fig. S1B) (46) was degraded particularly rapidly either during or shortly after its synthesis (before the chase) in reticulocyte extract, and was moderately short-lived afterward (postpulse t 1/2 of ∼140 min), in contrast to Val28-Capn1, which was nearly completely stable ( Fig. 5 C and D).…”

Section: (A) the Ubiquitin Reference Technique (Urt) (B)mentioning

confidence: 98%

“…Both Ca 2+ -activated calpain-1 (the catalytic subunit Capn1 plus the small subunit Capns1) and calpain-2 (Capn2 plus Capns1) can undergo a limited autoproteolysis (46,47). These N-terminal truncations of mouse Capn1, Capn2, and Capns1 generate, respectively, the Leu28-Capn1, Lys10-Capn2, and Asp142-Capns1 fragments, all of which bear destabilizing N-terminal residues (Figs.…”

Section: (A) the Ubiquitin Reference Technique (Urt) (B)mentioning

confidence: 99%

Calpain-generated natural protein fragments as short-lived substrates of the N-end rule pathway

Piatkov

Liu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Calpains are Ca 2+ -dependent intracellular proteases. We show here that calpain-generated natural C-terminal fragments of proteins that include G protein-coupled receptors, transmembrane ion channels, transcriptional regulators, apoptosis controllers, kinases, and phosphatases (Phe-GluN2a, Lys-Ica512, Arg-Ankrd2, Tyr-Grm1, Arg-Atp2b2, Glu-Bak, Arg-Igfbp2, Glu-IκBα, and Arg-cFos), are short-lived substrates of the Arg/N-end rule pathway, which targets destabilizing N-terminal residues. We also found that the identity of a fragment's N-terminal residue can change during evolution, but the residue's destabilizing activity is virtually always retained, suggesting selection pressures that favor a short half-life of the calpain-generated fragment. It is also shown that a self-cleavage of a calpain can result in an N-end rule substrate. Thus, the autoprocessing of calpains can control them by making active calpains short-lived. These and related results indicate that the Arg/N-end rule pathway mediates the remodeling of oligomeric complexes by eliminating protein fragments that are produced in these complexes through cleavages by calpains or other nonprocessive proteases. We suggest that this capability of the Arg/N-end rule pathway underlies a multitude of its previously known but mechanistically unclear functions.proteolysis | calpain substrates | ubiquitin

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Modulation of the Calpain Autoproteolysis by Calpastatin and Phospholipids

Cited by 86 publications

References 0 publications

Regulating cell migration: calpains make the cut

Regulating cell migration: calpains make the cut

Changes in intracellular localization of calpastatin during calpain activation

Calpain-generated natural protein fragments as short-lived substrates of the N-end rule pathway

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