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Titolo:
Regulation of the alpha-secretase ADAM10 by its prodomain and proprotein convertases
Autore:
Anders, A; Gilbert, S; Garten, W; Postina, R; Fahrenholz, F;
Indirizzi:
Univ Mainz, Inst Biochem, D-55128 Mainz, Germany Univ Mainz Mainz Germany D-55128 z, Inst Biochem, D-55128 Mainz, Germany Univ Marburg, Inst Virol, D-35037 Marburg, Germany Univ Marburg Marburg Germany D-35037 nst Virol, D-35037 Marburg, Germany
Titolo Testata:
FASEB JOURNAL
fascicolo: 8, volume: 15, anno: 2001,
pagine: NIL_39 - NIL_59
SICI:
0892-6638(200106)15:8<NIL_39:ROTAAB>2.0.ZU;2-Y
Fonte:
ISI
Lingua:
ENG
Soggetto:
AMYLOID-PRECURSOR PROTEIN; TRANS-GOLGI NETWORK; BETA-SECRETASE; INTRACELLULAR MATURATION; CYSTEINE SWITCH; PROHORMONE CONVERTASES; ALZHEIMERS-DISEASE; SNAKE-VENOM; PRO-REGION; CLEAVAGE;
Keywords:
PC7; furin; Alzheimer's disease; alpha-secretase; ADAM10;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
56
Recensione:
Indirizzi per estratti:
Indirizzo: Fahrenholz, F Univ Mainz, Inst Biochem, Becherweg 30, D-55128 Mainz, Germany Univ Mainz Becherweg 30 Mainz Germany D-55128 ainz, Germany
Citazione:
A. Anders et al., "Regulation of the alpha-secretase ADAM10 by its prodomain and proprotein convertases", FASEB J, 15(8), 2001, pp. NIL_39-NIL_59

Abstract

Ectodomain shedding of the Alzheimer's amyloid precursor protein is mediated by alpha- and beta -secretases, which, for their part, are also proteolytically processed. The disintegrin metalloproteinase ADAM10 is synthesized as a zymogen with a proprotein convertase (PC) recognition sequence betweenthe prodomain and the catalytic domain. In this study, we investigated therole of the prodomain in the regulation of the alpha -secretase activity of ADAM10. Overexpression of the proprotein convertases PC7 and furin in human embryonic kidney 293 cells revealed an increased ADAM10 maturation resulting in enhanced alpha -secretase-mediated processing of amyloid precursor protein. Mutation of the PC recognition sequence in ADAM10 as well as the use of a PC inhibitor and of the furin-deficient LoVo cell line confirmed the role of PCs, in particular, of PC7, in ADAM10 maturation and activation. Furthermore, we demonstrated that the prodomain of ADAM10 has a dual function. When coexpressed in trans as separate polypeptide, it inhibited the alpha -secretase activity of wild-type ADAM10. However, the prodomain acted asa chaperone and functionally rescued the alpha -secretase activity of a former inactive ADAM10 mutant lacking the prodomain. The results of our studysuggest new approaches to enhance the nonamyloidogenic alpha -secretase pathway.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 26/01/20 alle ore 17:15:02