A Structural Study of the Cytoplasmic Chaperone Effect of 14-3-3 Proteins on Ataxin-1

[Display omitted] •14-3-3 was postulated to prevent cytoplasmic aggregation of Ataxin-1.•Experimental support for an anti-aggregation effect of 14-3-3 on Ataxin-1 is provided.•Structural studies suggest 14-3-3 reduces Ataxin-1 dimerisation and further self-association.•Modulation of the 14-3-3/Ataxi...

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Vydané v:Journal of molecular biology Ročník 433; číslo 19; s. 167174
Hlavní autori: Leysen, Seppe, Burnley, Rebecca Jane, Rodriguez, Elizabeth, Milroy, Lech-Gustav, Soini, Lorenzo, Adamski, Carolyn J., Nitschke, Larissa, Davis, Rachel, Obsil, Tomas, Brunsveld, Lucas, Crabbe, Tom, Zoghbi, Huda Yahya, Ottmann, Christian, Davis, Jeremy Martin
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: Netherlands Elsevier Ltd 17.09.2021
Elsevier
Predmet:
14-3-3 Proteins - metabolism
Ataxin-1 - chemistry
Ataxin-1 - metabolism
Binding Sites
Cell Line
crystal structure
Crystallography, X-Ray
Cytoplasm - metabolism
dimerization
HDX-MS
HEK293 Cells
Humans
molecular biology
mutants
neurodegeneration
neurodegenerative diseases
Phosphorylation
protein aggregation
Protein Domains
Protein Multimerization
Protein Stability
SAXS
serine
pS
SUMO
DSS
SCA1
neurodegeneration
AXH domain
SAXS
HDX-MS
NLS
protein aggregation
crystal structure
DSG
ITC
polyQ
CIC
ISSN:0022-2836, 1089-8638, 1089-8638
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Shrnutí:[Display omitted] •14-3-3 was postulated to prevent cytoplasmic aggregation of Ataxin-1.•Experimental support for an anti-aggregation effect of 14-3-3 on Ataxin-1 is provided.•Structural studies suggest 14-3-3 reduces Ataxin-1 dimerisation and further self-association.•Modulation of the 14-3-3/Ataxin-1 interaction could provide a treatment for SCA1. Expansion of the polyglutamine tract in the N terminus of Ataxin-1 is the main cause of the neurodegenerative disease, spinocerebellar ataxia type 1 (SCA1). However, the C-terminal part of the protein – including its AXH domain and a phosphorylation on residue serine 776 – also plays a crucial role in disease development. This phosphorylation event is known to be crucial for the interaction of Ataxin-1 with the 14-3-3 adaptor proteins and has been shown to indirectly contribute to Ataxin-1 stability. Here we show that 14-3-3 also has a direct anti-aggregation or “chaperone” effect on Ataxin-1. Furthermore, we provide structural and biophysical information revealing how phosphorylated S776 in the intrinsically disordered C terminus of Ataxin-1 mediates the cytoplasmic interaction with 14-3-3 proteins. Based on these findings, we propose that 14-3-3 exerts the observed chaperone effect by interfering with Ataxin-1 dimerization through its AXH domain, reducing further self-association. The chaperone effect is particularly important in the context of SCA1, as it was previously shown that a soluble form of mutant Ataxin-1 is the major driver of pathology.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
ISSN:0022-2836
1089-8638
1089-8638
DOI:10.1016/j.jmb.2021.167174