A new human calpastatin skipped of the inhibitory region protects calpain-1 from inactivation and degradation

Bianca Sparatore, Marco Pedrazzi, Anna Garuti, Alice Franchi, Monica Averna, Alberto Ballestrero, Roberta De Tullio

Research output: Contribution to journalArticle

Abstract

Several human acute and chronic diseases involve calpain over-activation. However, the mechanistic linkages between the etiology and the progression of cell damages are not yet completely understood. Here we show that different human cells and tissues, including brain tumor specimens, cell lines of nerve origin, breast tumor samples and peripheral blood mononuclear cells from healthy donors, express a calpastatin form that lacks all the exons coding for the domains responsible of calpain inhibition. The open reading frame of this new form of calpastatin, named hcast 3-25, starts inside the L-domain (exons 2 and 3) and continues with the exons from 25 to 29 that code for the conserved C-terminal tail shared by all the full-length calpastatins. We have here observed that unlike the other calpastatins forms, that are predominantly Δ3 splice variants, hcast 3-25 is endowed with exon 3. At a functional level, recombinant hcast 3-25 operates as a positive modulator of calpain-1 in vitro by preventing 1) calpain-1-mediated proteolytic degradation of the activated enzyme and 2) binding to calpain-1 of inhibitory calpastatins that contain the L-domain. Thus hcast 3-25 can be considered as a novel member and possible modulator of the calpain/calpastatin system acting by a mechanism alternative to inhibition.

Original languageEnglish
Pages (from-to)1260-1271
Number of pages12
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1866
Issue number8
DOIs
Publication statusPublished - Aug 1 2019

Keywords

  • Calpain regulation
  • Calpastatin L-domain
  • hcast 3-25
  • Δ3-calpastatin

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'A new human calpastatin skipped of the inhibitory region protects calpain-1 from inactivation and degradation'. Together they form a unique fingerprint.

  • Cite this