Role of histidine interruption in mitigating the pathological effects of long polyglutamine stretches in SCA1: A molecular approach.
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.
Sen
Somdutta
S
Functional Genomics Unit, Institute of Genomics & Integrative Biology (formerly Centre for Biochemical Technology), CSIR, Delhi-110007, India.
Dash
Debasis
D
Pasha
Santosh
S
Brahmachari
Samir K
SK
D000595:Amino Acid Sequence; D000067696:Ataxin-1; D000067528:Ataxins; D019281:Dimerization; D006639:Histidine; D006801:Humans; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000502:physiology; D009687:Nuclear Proteins / Q000737:chemistry* / Q000502:physiology; D010455:Peptides / Q000737:chemistry*; D010641:Phenotype; D017433:Protein Structure, Secondary; D012995:Solubility; D012997:Solvents / Q000494:pharmacology; D013696:Temperature
C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D012997:Solvents; C097188:polyglutamine; D006639:Histidine