Peptides that activate the 20S proteasome by gate opening increased oxidized protein removal and reduced protein aggregation

Autor(es)

Dal Vechio, Francisco H. ^[1] ; Cerqueira, Fernanda ^[2] ; Augusto, Ohara ^[2] ; Lopes, Robson ^[3] ; Demasi, Marilene ^[1]

Afiliação do(s) autor(es)

^[1] Inst Butantan, Lab Bioquim & Biofis, BR-05503001 Sao Paulo - Brazil

^[2] Inst Butantan, Lab Especial Toxinol Aplicada, BR-05503001 Sao Paulo - Brazil

^[3] Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-01498 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Free Radical Biology and Medicine; v. 67, p. 304-313, FEB 2014.
• Citações Web of Science: 17

Resumo

The proteasome is a multicatalytic protease that is responsible for the degradation of the majority of intracellular proteins. Its role is correlated with several major regulatory pathways that are involved in cell cycle control, signaling, and antigen presentation, as well as in the removal of oxidatively damaged proteins. Although several proteasomal catalytic inhibitors have been described, very few activators have been reported to date. Some reports in the literature highlight the cellular protective effects of proteasome activation against oxidative stress and its effect on increased life span. In this work, we describe a peptide named proteasome-activating peptide I (PAP1), which increases the chymotrypsin-like proteasomal catalytic activity and, consequently, proteolytic rates both in vitro and in culture. PAPI proteasomal activation is mediated by the opening of the proteasomal catalytic chamber. We also demonstrate that the observed proteasomal activation protected cells from oxidative stress; further, PAP1 prevented protein aggregation in a cellular model of amyotrophic lateral sclerosis. The role of 20SPT gate opening underlying protection against oxidative stress was also explored in yeast cells. The present data indicate the importance of proteasomal activators as potential drugs for the treatment of pathologies associated with the impaired removal of damaged proteins, which is observed in many neurodegenerative diseases. (C) 2013 Elsevier Inc. All rights reserved. (AU)

• Processo FAPESP: 06/06969-0 - Estabelecimento de modelos em cultura celular para o estudo de moduladores do proteassomo 20S obtidos por prospecção
• Beneficiário: Marilene Demasi
• Modalidade de apoio: Auxílio à Pesquisa - Regular