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

Sen, Somdutta and Dash, Debasis and Pasha, Santosh and Brahmachari, Samir K. (2009) Role of histidine interruption in mitigating the pathological effects of long polyglutamine stretches in SCA1: A molecular approach. Role of histidine interruption in mitigating the pathological effects of long polyglutamine stretches in SCA1: A molecular approach, 12 (5). pp. 953-962.

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Abstract

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 (Q(12)HQHQ(12)HQHQ(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 (Q(12)HQHQ(12)HQHQ(12)) and without (Q(42)) interruptions is presented here. Q(12)HQHQ(12)HQHQ(12) displays greater solubility and lesser aggregation propensity compared to uninterrupted Q(42) as well as much shorter Q(22). The solvent and temperature-driven conformational transitions (beta structure <--> random coil --> alpha 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.

Item Type: Article
Subjects: BI Bioinformatics > BI1 Bioinformatics (General)
Divisions: Faculty of Genomics and Molecular Medicine > School of Genomics and Molecular Medicine
Depositing User: Raghu MV
Date Deposited: 17 Jan 2012 12:20
Last Modified: 08 Feb 2013 09:48
URI: http://openaccess.igib.res.in/id/eprint/129

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