Abstract
Polyglutamine (polyQ) repeat disorders are caused by the expansion of CAG tracts in certain genes, resulting in transcription of proteins with abnormally long polyQ inserts. When these inserts expand beyond 35-45 glutamines, affected proteins form toxic aggregates, leading to neuron death. Chymotrypsin inhibitor 2 (CI2) with an inserted glutamine repeat has previously been used to model polyQ-mediated aggregation in vitro. However, polyQ insertion lengths in these studies have been kept below the pathogenic threshold. We perform molecular dynamics simulations to study monomer folding dynamics and dimer formation in CI2-polyQ chimeras with insertion lengths of up to 80 glutamines. Our model recapitulates the experimental results of previous studies of chimeric CI2 proteins, showing high folding cooperativity of monomers as well as protein association via domain swapping. Surprisingly, for chimeras with insertion lengths above the pathogenic threshold, monomer folding cooperativity decreases and the dominant mode for dimer formation becomes interglutamine hydrogen bonding. These results support a mechanism for pathogenic polyQ-mediated aggregation, in which expanded polyQ tracts destabilize affected proteins and promote the formation of partially unfolded intermediates. These unfolded intermediates form aggregates through associations by interglutamine interactions.
Highlights
The polyglutamine3 repeat disorders are a family of inherited disorders characterized by progressive neurodegeneration, as well as the formation of intracellular protein aggregates
Because the Chymotrypsin inhibitor 2 (CI2)-polyQ model system has been explored by previous experimental [3, 4, 12, 13, 15,16,17,18] and theoretical [19] studies, we systematically studied the conformational dynamics of chimeric CI2-polyQ proteins with a variety of insert lengths (4 – 80 glutamines), including glutamine tracts longer than the pathogenic threshold
We observed that the dominant mode of dimer formation in CI2 chimeras change from domain swapping to interglutamine interactions as polyQ insert length increased beyond the pathogenic threshold
Summary
The polyglutamine (polyQ) repeat disorders are a family of inherited disorders characterized by progressive neurodegeneration, as well as the formation of intracellular protein aggregates. Because the CI2-polyQ model system has been explored by previous experimental [3, 4, 12, 13, 15,16,17,18] and theoretical [19] studies, we systematically studied the conformational dynamics of chimeric CI2-polyQ proteins with a variety of insert lengths (4 – 80 glutamines), including glutamine tracts longer than the pathogenic threshold. We observed that the dominant mode of dimer formation in CI2 chimeras change from domain swapping to interglutamine interactions as polyQ insert length increased beyond the pathogenic threshold. The observation of the length-dependent folding/aggregation behavior in the polyQ-inserted CI2 protein, a non-amyloidogenic protein, supports a mechanism for polyQ-mediated aggregation in which insert length determines the degree of intra- versus interchain interactions: at small insert lengths, the destabilization induced by the introduction of polyglutamine leads to domain-swapping whereas at large insert lengths (greater than pathogenic threshold) interchain glutamine-glutamine interactions dominate and lead to aggregation
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