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Titolo:
Enteroviral protease 2A directly cleaves dystrophin and is inhibited by a dystrophin-based substrate analogue
Autore:
Badorff, C; Berkely, N; Mehrotra, S; Talhouk, JW; Rhoads, RE; Knowlton, KU;
Indirizzi:
Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA Univ Calif San Diego La Jolla CA USA 92093 pt Med, La Jolla, CA 92093 USA Louisiana State Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, Shreveport, LA 71130 USA Louisiana State Univ Shreveport LA USA 71130 ol, Shreveport, LA 71130 USA Enzyme Syst Prod, Livermore, CA 94550 USA Enzyme Syst Prod Livermore CA USA 94550 yst Prod, Livermore, CA 94550 USA
Titolo Testata:
JOURNAL OF BIOLOGICAL CHEMISTRY
fascicolo: 15, volume: 275, anno: 2000,
pagine: 11191 - 11197
SICI:
0021-9258(20000414)275:15<11191:EP2DCD>2.0.ZU;2-P
Fonte:
ISI
Lingua:
ENG
Soggetto:
LINKED DILATED CARDIOMYOPATHY; DUCHENNE MUSCULAR-DYSTROPHY; HEART-FAILURE; ROD DOMAIN; POLIOVIRUS; RHINOVIRUS; MICE; SITE; IMMUNODEFICIENCY; INFECTION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
40
Recensione:
Indirizzi per estratti:
Indirizzo: Knowlton, KU Univ Calif San Diego, Dept Med, 9500 Gilman Dr, La Jolla, CA 92093 USA Univ Calif San Diego 9500 Gilman Dr La Jolla CA USA 92093 USA
Citazione:
C. Badorff et al., "Enteroviral protease 2A directly cleaves dystrophin and is inhibited by a dystrophin-based substrate analogue", J BIOL CHEM, 275(15), 2000, pp. 11191-11197

Abstract

Enteroviruses such as Coxsackievirus B3 can cause dilated cardiomyopathy through unknown pathological mechanism(s). Dystrophin is a large extrasarcomeric cytoskeletal protein whose genetic deficiency causes hereditary dilated cardiomyopathy, In addition, we have recently shown that dystrophin is proteolytically cleaved by the Coxsackievirus protease 2A leading to functional impairment and morphological disruption. However, the mechanism of dystrophin cleavage and the exact cleavage site remained to be identified. Antibody epitope mapping of endogenous dystrophin indicated protease 2A-mediatedcleavage at the site in the hinge 3 region predicted by a neural network algorithm (human, amino acid 2434; mouse, amino acid 2427). Using site-directed mutagenesis, peptide sequencing, and fluorescence resonance energy transfer assays with recombinant dystrophin, we demonstrate that this putative site in mouse and human dystrophin is a direct substrate for the Coxsackieviral protease 2A both in vitro and in vivo. The substrate analogue proteaseinhibitor z-LSTT-fmk was designed based on the dystrophin sequence that interacts with the protease 2A and was found to have an IC50 of 550 nM in vitro, Dystrophin is the first cellular substrate of the enteroviral protease 2A that was identified using by a bioinformatic approach and for which the cleavage site was molecularly mapped within living cells.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 29/03/20 alle ore 15:08:17