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Role of histidine interruption in mitigating the pathological effects of long polyglutamine stretches in SCA1: A molecular approach

Functional Genomics Unit, Institute of Genomics & Integrative Biology (formerly Centre for Biochemical Technology), CSIR, Delhi-110007, India

Reprint requests to: Samir K. Brahmachari, Institute of Genomics & Integrative Biology (formerly Centre for Biochemical Technology), CSIR, Mall Road, Delhi-110007, India; e-mail: skb{at}cbt.res.in; fax: 91-11-27667471.

Polyglutamine expansions, leading to aggregation, have been implicated in various neurodegenerative disorders. The range of repeats observed in normal individuals in most of these diseases is 19–36, whereas mutant proteins carry 40–81 repeats. In one such disorder, spinocerebellar ataxia (SCA1), it has been reported that certain individuals with expanded polyglutamine repeats in the disease range (Q₁₂HQHQ₁₂HQHQ_14/15) but with histidine interruptions were found to be phenotypically normal. To establish the role of histidine, a comparative study of conformational properties of model peptide sequences with (Q₁₂HQHQ₁₂HQHQ₁₂) and without (Q₄₂) interruptions is presented here. Q₁₂HQHQ₁₂HQHQ₁₂ displays greater solubility and lesser aggregation propensity compared to uninterrupted Q₄₂ as well as much shorter Q₂₂. The solvent and temperature-driven conformational transitions (ß structure random coil helix) displayed by these model polyQ stretches is also discussed in the present report. The study strengthens our earlier hypothesis of the importance of histidine interruptions in mitigating the pathogenicity of expanded polyglutamine tract at the SCA1 locus. The relatively lower propensity for aggregation observed in case of histidine interrupted stretches even in the disease range suggests that at a very low concentration, the protein aggregation in normal cells, is possibly not initiated at all or the disease onset is significantly delayed. Our present study also reveals that besides histidine interruption, proline interruption in polyglutamine stretches can lower their aggregation propensity.

Keywords: Aggregation; ß-hairpin; circular dichroism; histidine interruption; polyglutamines; SCA1; TFE

Abbreviations: Q, glutamine • H, histidine • P, proline • Poly Q, polyglutamine • TFE, trifluoroethanol • HFIP, hexafluoroisopropanol • SSC buffer, sodium chloride/sodium citrate buffer, MALDI-ToF, matrix assisted laser desorption ionization-time of flight • HPLC, high performance liquid chromatography

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