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.
Authors	Rajesh P Menon, Daniel Soong, Cesira de Chiara, Mark R Holt, Narayana Anilkumar, Annalisa Pastore
Journal	Scientific reports (Sci Rep) Vol. 2 Pg. 919 ( 2012) ISSN: 2045-2322 [Electronic] England
PMID	23213356 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	14-3-3 Proteins ATXN1 protein, human Ataxin-1 Ataxins Nerve Tissue Proteins Nuclear Proteins Recombinant Fusion Proteins Ribonucleoproteins Splicing Factor U2AF U2AF2 protein, human Serine
Topics	14-3-3 Proteins (chemistry, genetics, metabolism) Animals Ataxin-1 Ataxins COS Cells Cell Nucleus (metabolism) Chlorocebus aethiops Fluorescence Resonance Energy Transfer Genes, Reporter Humans Mutation (genetics) Nerve Tissue Proteins (chemistry, genetics, metabolism) Nuclear Proteins (chemistry, genetics, metabolism) Phosphorylation Protein Conformation Recombinant Fusion Proteins (genetics, metabolism) Ribonucleoproteins (chemistry, genetics, metabolism) Serine (chemistry, genetics, metabolism) Splicing Factor U2AF

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