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An Intrinsically Disordered Region of the Acetyltransferase p300 with Similarity to Prion-Like Domains Plays a Role in Aggregation
Kirilyuk, A Shimoji, M Catania, J Sahu, G Pattabiraman, N Giordano, A Albanese, C Mocchetti, I Toretsky, JA Uversky, VN
Kirilyuk, A
Shimoji, M
Catania, J
Sahu, G
Pattabiraman, N
Giordano, A
Albanese, C
Mocchetti, I
Toretsky, JA
Uversky, VN
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Genre
Journal Article
Date
2012-11-01
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Committee member
Group
Department
Subject
Alternative Splicing
Amino Acid Sequence
Animals
Autophagy
COS Cells
Chlorocebus aethiops
Down-Regulation
Humans
Lewy Bodies
Molecular Sequence Data
Neoplasms
Neurodegenerative Diseases
Oxidative Stress
Parkinson Disease
Prions
Protein Denaturation
Protein Folding
Protein Structure, Tertiary
Sequence Homology, Amino Acid
alpha-Synuclein
p300-CBP Transcription Factors
Amino Acid Sequence
Animals
Autophagy
COS Cells
Chlorocebus aethiops
Down-Regulation
Humans
Lewy Bodies
Molecular Sequence Data
Neoplasms
Neurodegenerative Diseases
Oxidative Stress
Parkinson Disease
Prions
Protein Denaturation
Protein Folding
Protein Structure, Tertiary
Sequence Homology, Amino Acid
alpha-Synuclein
p300-CBP Transcription Factors
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DOI
10.1371/journal.pone.0048243
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. © 2012 Kirilyuk et al.
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PLoS ONE
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