title: Peptides that activate the 20S proteasome by gate opening increased oxidized protein removal and reduced protein aggregation.
abstract: 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 1 (PAP1), which increases the chymotrypsin-like proteasomal catalytic activity and, consequently, proteolytic rates both in vitro and in culture. PAP1 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.
authors.affiliation: Laboratório de Bioquímica e Biofísica, Instituto Butantan, São Paulo, SP 05503-001, Brazil.
authors.forename: Francisco H
authors.initials: FH
authors.lastname: Dal Vechio
authors.affiliation: Laboratório Especial de Toxinologia Aplicada, Instituto Butantan, São Paulo, SP 05503-001, Brazil.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Cerqueira
authors.affiliation: Laboratório Especial de Toxinologia Aplicada, Instituto Butantan, São Paulo, SP 05503-001, Brazil.
authors.forename: Ohara
authors.initials: O
authors.lastname: Augusto
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil.
authors.forename: Robson
authors.initials: R
authors.lastname: Lopes
authors.affiliation: Laboratório de Bioquímica e Biofísica, Instituto Butantan, São Paulo, SP 05503-001, Brazil. Electronic address: marimasi@butantan.gov.br.
authors.forename: Marilene
authors.initials: M
authors.lastname: Demasi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D008969:Molecular Sequence Data; D009474:Neurons / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D000073718:Pancreatitis-Associated Proteins; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism*; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological / Q000517:prevention & control*; D059748:Proteolysis; D011817:Rabbits; D012441:Saccharomyces cerevisiae / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D020536:Enzyme Activators; D000073718:Pancreatitis-Associated Proteins; D010455:Peptides; D066329:Protein Aggregates; C000612141:REG3A protein, human; D029701:Saccharomyces cerevisiae Proteins; D046988:Proteasome Endopeptidase Complex
keywords: ALS; Free radicals; Proteasome; Protein aggregation; Protein oxidation; Therapeutic peptides