title: An intrinsically disordered region of the acetyltransferase p300 with similarity to prion-like domains plays a role in aggregation.
abstract: Several human diseases including neurodegenerative disorders and cancer are associated with abnormal accumulation and aggregation of misfolded proteins. Proteins with high tendency to aggregate include the p53 gene product, TAU and alpha synuclein. The potential toxicity of aberrantly folded proteins is limited via their transport into intracellular sub-compartments, the aggresomes, where misfolded proteins are stored or cleared via autophagy. We have identified a region of the acetyltransferase p300 that is highly disordered and displays similarities with prion-like domains. We show that this region is encoded as an alternative spliced variant independently of the acetyltransferase domain, and provides an interaction interface for various misfolded proteins, promoting their aggregation. p300 enhances aggregation of TAU and of p53 and is a component of cellular aggregates in both tissue culture cells and in alpha-synuclein positive Lewy bodies of patients affected by Parkinson disease. Down-regulation of p300 impairs aggresome formation and enhances cytotoxicity induced by misfolded protein stress. These data unravel a novel activity of p300, offer new insights into the function of disordered domains and implicate p300 in pathological aggregation that occurs in neurodegeneration and cancer.
authors.affiliation: Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington, District of Columbia, United States of America.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kirilyuk
authors.forename: Mika
authors.initials: M
authors.lastname: Shimoji
authors.forename: Jason
authors.initials: J
authors.lastname: Catania
authors.forename: Geetaram
authors.initials: G
authors.lastname: Sahu
authors.forename: Nagarajan
authors.initials: N
authors.lastname: Pattabiraman
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordano
authors.forename: Christopher
authors.initials: C
authors.lastname: Albanese
authors.forename: Italo
authors.initials: I
authors.lastname: Mocchetti
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Toretsky
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Uversky
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Avantaggiati
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001343:Autophagy; D019556:COS Cells; D002522:Chlorocebus aethiops; D015536:Down-Regulation; D006801:Humans; D016631:Lewy Bodies / Q000378:metabolism; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000378:metabolism; D011328:Prions / Q000737:chemistry; D011489:Protein Denaturation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D051844:alpha-Synuclein / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000737:chemistry* / Q000502:physiology; D000099224:p300-CBP-Associated Factor
chemical_list: D011328:Prions; D051844:alpha-Synuclein; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor