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Titolo:
Recombinant forms of tetanus toxin engineered for examining and exploitingneuronal trafficking pathways
Autore:
Li, Y; Foran, P; Lawrence, G; Mohammed, N; Chan-Kwo-Chion, CKN; Lisk, G; Aoki, R; Dolly, O;
Indirizzi:
Univ London Imperial Coll Sci Technol & Med, Dept Biochem, London SW7 2AZ,England Univ London Imperial Coll Sci Technol & Med London England SW7 2AZ gland Allergan Pharmaceut Inc, Irvine, CA 92623 USA Allergan Pharmaceut Inc Irvine CA USA 92623 eut Inc, Irvine, CA 92623 USA
Titolo Testata:
JOURNAL OF BIOLOGICAL CHEMISTRY
fascicolo: 33, volume: 276, anno: 2001,
pagine: 31394 - 31401
SICI:
0021-9258(20010817)276:33<31394:RFOTTE>2.0.ZU;2-P
Fonte:
ISI
Lingua:
ENG
Soggetto:
RETROGRADE AXONAL-TRANSPORT; BOTULINUM NEUROTOXIN-A; CENTRAL-NERVOUS-SYSTEM; HEAVY-CHAIN; NEUROTRANSMITTER RELEASE; INTERCHAIN DISULFIDE; TRANSMITTER RELEASE; LIMITED PROTEOLYSIS; ESCHERICHIA-COLI; LIGHT-CHAIN;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
43
Recensione:
Indirizzi per estratti:
Indirizzo: Dolly, O Univ London Imperial Coll Sci Technol & Med, Dept Biochem, LondonSW7 2AZ,England Univ London Imperial Coll Sci Technol & Med London England SW7 2AZ
Citazione:
Y. Li et al., "Recombinant forms of tetanus toxin engineered for examining and exploitingneuronal trafficking pathways", J BIOL CHEM, 276(33), 2001, pp. 31394-31401

Abstract

Tetanus toxin is a fascinating, multifunctional protein that binds to peripheral neurons, undergoes retrograde transport and trans-synaptic transfer to central inhibitory neurons where it blocks transmitter release, thereby,causing spastic paralysis. As a pre-requisite for exploiting its unique trafficking properties, a novel recombinant single chain was expressed at a high level in Eacherichia coli as a soluble, easily purifiable protein. It could be activated with enterokinase to produce a di-chain that matched native toxin in terms of proteolytic and neuroinhibitory activities, as well asinduction of spastic paralysis in mice. Importantly, nicking was not essential for protease activity. Substitution of GIU234 by Ala created a protease-deficient atoxic form, which blocked the neuroparalytic action of tetanustoxin in vitro, with equal potency to its heavy chain; but, the mutant proved > 30-fold more potent in preventing tetanus in mice. This observation unveils differences between the intoxication processes resulting from retrograde transport of toxin in vivo and its local uptake into peripheral or central nerves in vitro, dispelling a popularly held belief that the heavy chain is the sole determinant for efficient trafficking. Thus, this innocuous mutant may be a useful vehicle, superior to the heavy chain, for drug delivery to central neurons.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 29/03/20 alle ore 09:34:44