The importance of serine 776 in Ataxin-1 partner selection:: A FRET Analysis

Rajesh P. Menon; Daniel Soong; Cesira de Chiara; Mark R. Holt; Narayana Anilkumar; Annalisa Pastore

doi:10.1038/srep00919

The importance of serine 776 in Ataxin-1 partner selection: A FRET Analysis

Rajesh P. Menon^*, Daniel Soong, Cesira de Chiara, Mark R. Holt, Narayana Anilkumar, Annalisa Pastore

^*Corresponding author for this work

Cardiovascular Sciences

National Institute for Medical Research

Research output: Contribution to journal › Article › peer-review

12 Citations (Scopus)

Abstract

Anomalous expansion of a polymorphic tract in Ataxin-1 causes the autosomal dominant spinocerebellar ataxia type 1. In addition to polyglutamine expansion, requirements for development of pathology are phosphorylation of serine 776 in Ataxin-1 and nuclear localization of the protein. The phosphorylation state of serine 776 is also crucial for selection of the Ataxin-1 multiple partners. Here, we have used FRET for an in cell study of the interaction of Ataxin-1 with the spliceosome-associated U2AF65 and the adaptor 14-3-3 proteins. Using wild-type Ataxin-1 and Ser776 mutants to a phosphomimetic aspartate and to alanine, we show that U2AF65 binds Ataxin-1 in a Ser776 phosphorylation independent manner whereas 14-3-3 interacts with phosphorylated wild-type Ataxin-1 but not with the mutants. These results indicate that Ser776 acts as the molecular switch that discriminates between normal and aberrant function and that phosphomimetics is not a generally valid approach whose applicability should be carefully validated.

Original language	English
Article number	919
Pages (from-to)	N/A
Number of pages	7
Journal	Scientific Reports
Volume	2
Issue number	N/A
DOIs	https://doi.org/10.1038/srep00919
Publication status	Published - 4 Dec 2012

Keywords

POLYGLUTAMINE-INDUCED DISEASE
SCA1 TRANSGENIC MICE
AXH DOMAIN
MEDIATES NEURODEGENERATION
NUCLEAR-LOCALIZATION
MUTANT ATAXIN-1
PROTEIN
PHOSPHORYLATION
TYPE-1
AGGREGATION

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title = "The importance of serine 776 in Ataxin-1 partner selection:: A FRET Analysis",

abstract = "Anomalous expansion of a polymorphic tract in Ataxin-1 causes the autosomal dominant spinocerebellar ataxia type 1. In addition to polyglutamine expansion, requirements for development of pathology are phosphorylation of serine 776 in Ataxin-1 and nuclear localization of the protein. The phosphorylation state of serine 776 is also crucial for selection of the Ataxin-1 multiple partners. Here, we have used FRET for an in cell study of the interaction of Ataxin-1 with the spliceosome-associated U2AF65 and the adaptor 14-3-3 proteins. Using wild-type Ataxin-1 and Ser776 mutants to a phosphomimetic aspartate and to alanine, we show that U2AF65 binds Ataxin-1 in a Ser776 phosphorylation independent manner whereas 14-3-3 interacts with phosphorylated wild-type Ataxin-1 but not with the mutants. These results indicate that Ser776 acts as the molecular switch that discriminates between normal and aberrant function and that phosphomimetics is not a generally valid approach whose applicability should be carefully validated.",

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T2 - A FRET Analysis

AU - Menon, Rajesh P.

AU - Soong, Daniel

AU - de Chiara, Cesira

AU - Holt, Mark R.

AU - Anilkumar, Narayana

AU - Pastore, Annalisa

PY - 2012/12/4

Y1 - 2012/12/4

N2 - Anomalous expansion of a polymorphic tract in Ataxin-1 causes the autosomal dominant spinocerebellar ataxia type 1. In addition to polyglutamine expansion, requirements for development of pathology are phosphorylation of serine 776 in Ataxin-1 and nuclear localization of the protein. The phosphorylation state of serine 776 is also crucial for selection of the Ataxin-1 multiple partners. Here, we have used FRET for an in cell study of the interaction of Ataxin-1 with the spliceosome-associated U2AF65 and the adaptor 14-3-3 proteins. Using wild-type Ataxin-1 and Ser776 mutants to a phosphomimetic aspartate and to alanine, we show that U2AF65 binds Ataxin-1 in a Ser776 phosphorylation independent manner whereas 14-3-3 interacts with phosphorylated wild-type Ataxin-1 but not with the mutants. These results indicate that Ser776 acts as the molecular switch that discriminates between normal and aberrant function and that phosphomimetics is not a generally valid approach whose applicability should be carefully validated.

AB - Anomalous expansion of a polymorphic tract in Ataxin-1 causes the autosomal dominant spinocerebellar ataxia type 1. In addition to polyglutamine expansion, requirements for development of pathology are phosphorylation of serine 776 in Ataxin-1 and nuclear localization of the protein. The phosphorylation state of serine 776 is also crucial for selection of the Ataxin-1 multiple partners. Here, we have used FRET for an in cell study of the interaction of Ataxin-1 with the spliceosome-associated U2AF65 and the adaptor 14-3-3 proteins. Using wild-type Ataxin-1 and Ser776 mutants to a phosphomimetic aspartate and to alanine, we show that U2AF65 binds Ataxin-1 in a Ser776 phosphorylation independent manner whereas 14-3-3 interacts with phosphorylated wild-type Ataxin-1 but not with the mutants. These results indicate that Ser776 acts as the molecular switch that discriminates between normal and aberrant function and that phosphomimetics is not a generally valid approach whose applicability should be carefully validated.

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KW - MUTANT ATAXIN-1

KW - PROTEIN

KW - PHOSPHORYLATION

KW - TYPE-1

KW - AGGREGATION

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M3 - Article

SN - 2045-2322

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JO - Scientific Reports

JF - Scientific Reports

IS - N/A

M1 - 919

ER -

The importance of serine 776 in Ataxin-1 partner selection: A FRET Analysis

Abstract

Keywords

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