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

Protein Science - Tập 12 Số 5 - Trang 953-962 - 2003
Somdutta Sen1, Debasis Dash1, Santosh Pasha1, Samir K. Brahmachari2
1Functional Genomics Unit, Institute of Genomics & Integrative Biology (formerly Centre for Biochemical Technology), CSIR, Delhi‐110007, India
2Institute of Genomics & Integrative Biology (formerly Centre for Biochemical Technology), CSIR, Mall Road, Delhi‐110007, India; fax: 91‐11‐27667471.

Tóm tắt

AbstractPolyglutamine 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 (Q12HQHQ12HQHQ14/15) 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 (β structure ↔ random coil → α 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.

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Protein Science

Tập 12 Số 5

953-962

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