Protein binding of a DRPLA family through arginine-glutamic acid dipeptiderepeats is enhanced by extended polyglutamine

Dentatorubral-pallidoluysian atrophy (DRPLA) is one of the hereditary neuro degenerative disorders caused by expansion of CAG/glutamine repeats. To inv estigate the normal function of the DRPLA gene and the pathogenic mechanism of neuron death in specific areas of the brain, we isolated and analyzed a gene that shares a notable motif with DRPLA, arginine-glutamic acid (RE) d ipeptide repeats. The gene isolated, designated RERE, has an open reading f rame of 1566 amino acids, of which the C-terminal portion has 67% homology to DRPLA, whereas the N-terminal portion is distinctive. RERE also contains arginine-aspartic acid (RD) dipeptide repeats and putative nuclear localiz ation signal sequences, but no polyglutamine tracts. RERE is expressed at a low level in most tissues examined. Immunoprecipitation and in vitro bindi ng assays demonstrate that the DRPLA and RERE proteins bind each other, for which one of the RE repeats has a primary role, and extended polyglutamine enhances the binding. With engineered constructs fused with a tag, the RER E protein localized predominantly in the nucleus. Moreover, when RERE is ov erexpressed, the distribution of endogenous DRPLA protein alters from the d iffused to the speckled pattern in the nucleus so as to co-localize with RE RE. More RERE protein is recruited into nuclear aggregates of the DRPLA pro tein with extended polyglutamine than into those of pure polyglutamine. The se results reveal a function for the DRPLA protein in the nucleus and the R E repeat in the protein-protein interaction.