Proteins with Intrinsically Disordered Domains Are Preferentially Recruited to Polyglutamine Aggregates

PloS One
Maggie P WearFrank P Shewmaker

Abstract

Intracellular protein aggregation is the hallmark of several neurodegenerative diseases. Aggregates formed by polyglutamine (polyQ)-expanded proteins, such as Huntingtin, adopt amyloid-like structures that are resistant to denaturation. We used a novel purification strategy to isolate aggregates formed by human Huntingtin N-terminal fragments with expanded polyQ tracts from both yeast and mammalian (PC-12) cells. Using mass spectrometry we identified the protein species that are trapped within these polyQ aggregates. We found that proteins with very long intrinsically-disordered (ID) domains (≥ 100 amino acids) and RNA-binding proteins were disproportionately recruited into aggregates. The removal of the ID domains from selected proteins was sufficient to eliminate their recruitment into polyQ aggregates. We also observed that several neurodegenerative disease-linked proteins were reproducibly trapped within the polyQ aggregates purified from mammalian cells. Many of these proteins have large ID domains and are found in neuronal inclusions in their respective diseases. Our study indicates that neurodegenerative disease-associated proteins are particularly vulnerable to recruitment into polyQ aggregates via their ID domains. Als...Continue Reading

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Citations

Dec 18, 2015·Scientific Reports·Genrikh V SerpionovMichael D Ter-Avanesyan
Apr 3, 2016·Brain Research·Navit Ogen-ShternGerardo Z Lederkremer
Aug 8, 2018·International Journal of Molecular Sciences·Stanislav A BondarevGalina A Zhouravleva
Nov 4, 2016·G3 : Genes - Genomes - Genetics·Michelle D LeachLeah E Cowen
Feb 15, 2017·EMBO Reports·Sandra Malmgren HillThomas Nyström
Aug 17, 2019·Journal of Neurochemistry·Erich E WankerSigrid Schnoegl
Oct 26, 2018·FEMS Microbiology Reviews·Ario de MarcoAntonio Villaverde
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Aug 21, 2019·Ageing Research Reviews·Paramita ChaudhuriKarunakar Kar
Mar 25, 2021·Molecular Brain·Shun KubotaFumiaki Tanaka
Jun 10, 2021·Cell Death & Disease·Adriana MarceloClévio Nóbrega
Sep 25, 2017·Journal of the American Chemical Society·John B WarnerHilal A Lashuel

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Methods Mentioned

BETA
electrophoresis
pull-down
Fluorescence microscopy
Confocal microscopy
following
ubiquitination
transgenic

Software Mentioned

IUPred
Zen
Proteome Discoverer
MS2
Graphpad
Scaffold
FoldIndex
Mascot
Excel

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