The Length Dependence of the PolyQ-mediated Protein Aggregation

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.

Molecular Mechanism of Huntington’s Disease — A Computational Perspective

“…Moreover, it was demonstrated that the dominant mode for dimer formation was inter Qs H-bonding (Barton et al 2007). The aggregation of model polyQ peptides was also investigated via MD simulations with a simplified model of polyQ (Marchut & Hall 2006a, 2006b, 2007.…”

Cerebellar Disorders—At the Crossroad of Molecular Pathways and Diagnosis

“…Proteins form aggregates which contribute to neuronal loss. Expanded polyQ tracts participate in the formation of partially unfolded proteins [4]. Neurological deficits of polyQ repeat disorders appear for expanding tracts exceeding the critical value of 35-45 glutamines [4,5].…”

“…Expanded polyQ tracts participate in the formation of partially unfolded proteins [4]. Neurological deficits of polyQ repeat disorders appear for expanding tracts exceeding the critical value of 35-45 glutamines [4,5]. Several models have been developed to recapitulate the molecular mechanisms occurring in cerebellar disorders, ranging from in vitro studies to complex animal models, each of them having advantages and disadvantages for translational research [6].…”

“…Currently, 28 SCAs are identified [3]. In several SCAs, the expansion of CAG tracts in certain genes results in transcription of proteins with abnormally long polyQ (polyglutamine) inserts [4]. Such a mechanism is shared with Huntington's disease with stroke-like episodes) MEERF (myoclonus epilepsy with ragged red fibers).…”

Communication: Conformation state diagram of polypeptides: A chain length induced α-β transition

“…12 This is manifested in a pronounced stepwise T -dependence of the internal energy, resulting in a sharp maximum in the heat capacity, 7,17 Fig. 3(b) for N = 20, 30, and 50.…”