Dataset Information

Length-Dependent Structural Transformations of Huntingtin PolyQ Domain Upon Binding to 2D-Nanomaterials.

ABSTRACT: There is a strong negative correlation between the polyglutamine (polyQ) domain length (Q-length) in the intrinsically disordered Huntingtin protein (Htt) exon-1 and the age of onset of Huntington's disease (HD). PolyQ of Q-length longer than 40 has the propensity of forming very compact aggregate structures, leading to HD at full penetrance. Recent advances in nanobiotechnology provided a new platform for the development of novel diagnosis and therapeutics. Here, we explore the possibility of utilizing 2D-nanomaterials to inhibit the formation of supercompact polyQ structures through the so-called "folding-upon-binding" where the protein structure is dependent on the binding substrate. Using molecular dynamics simulations, we characterize two polyQ peptides with Q-length of 22 (Q22, normal length) and 46 (Q46, typical length causing HD) binding to both graphene and molybdenum disulfide (MoS2) nanosheets, which have been applied as antibacterial or anticancer agents. Upon binding, Q22 unfolds and elongates on both grapheme and MoS2 surfaces, regardless of its initial conformation, with graphene showing slightly stronger effect. In contrast, initially collapsed Q46 remains mostly collapsed within our simulation time on both nanosheets even though they do provide some "stretching" to Q46 as well. Further analyses indicate that the hydrophobic nature of graphene/MoS2 promotes the stretching of polyQ on nanosheets. However, there is strong competition with the intra-polyQ interactions (mainly internal hydrogen bonds) leading to the disparate folding/binding behaviors of Q22 and Q46. Our results present distinct Q-length specific behavior of the polyQ domain upon binding to two types of 2D-nanomaterials which holds clinical relevance for Huntington's disease.

SUBMITTER: Feng M

PROVIDER: S-EPMC7189795 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Length-Dependent Structural Transformations of Huntingtin PolyQ Domain Upon Binding to 2D-Nanomaterials.

Feng Mei M Bell David R DR Wang Zhenhua Z Zhang Wei W

Frontiers in chemistry 20200421

There is a strong negative correlation between the polyglutamine (polyQ) domain length (Q-length) in the intrinsically disordered Huntingtin protein (Htt) exon-1 and the age of onset of Huntington's disease (HD). PolyQ of Q-length longer than 40 has the propensity of forming very compact aggregate structures, leading to HD at full penetrance. Recent advances in nanobiotechnology provided a new platform for the development of novel diagnosis and therapeutics. Here, we explore the possibility of u ...[more]

PMID: 32391325

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Project description:Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by an expansion of a polyglutamine tract within the ATXN1 gene. Normal alleles have been reported to range from 6 to 35 repeats, intermediate alleles from 36 to 38 repeats and fully penetrant pathogenic alleles have at least 39 repeats. This distribution was based on relatively few samples and the narrow intermediate range makes the accuracy of the repeat sizing crucial for interpreting and reporting diagnostic tests, which can vary between laboratories. Here, we examine the distribution of 6378 SCA1 chromosomes and identify a very late onset SCA1 family with a fully penetrant uninterrupted pathogenic allele containing 38 repeats. This finding supports the theory that polyQ toxicity is related to the increase of the length of the inherited tracts and not as previously hypothesized to the structural transition occurring above a specific threshold. In addition, the threshold of toxicity shifts to a shorter polyQ length with the increase of the lifespan in SCA1. Furthermore, we show that SCA1 intermediate alleles have a different behavior compared to the other polyglutamine disorders as they do not show reduced penetrance when uninterrupted. Therefore, the pathogenic mechanism in SCA1 is distinct from other cytosine-adenine-guanine (CAG) repeat disorders. Accurately sizing repeats is paramount in precision medicine and can be challenging particularly with borderline alleles. We examined plasmids containing cloned CAG repeat tracts alongside a triplet repeat primed polymerase chain reaction (TP PCR) CAG repeat ladder to improve accuracy in repeat sizing by fragment analysis. This method accurately sizes the repeats irrespective of repeat composition or length. We also improved the model for calculating repeat length from fragment analysis sizing by fragment analyzing 100 cloned repeats of known size. Therefore, we recommend these methods for accurately sizing repeat lengths and restriction enzyme digestion to identify interruptions for interpretation of a given allele's pathogenicity.

Dataset Information

Length-Dependent Structural Transformations of Huntingtin PolyQ Domain Upon Binding to 2D-Nanomaterials.

Publications

Length-Dependent Structural Transformations of Huntingtin PolyQ Domain Upon Binding to 2D-Nanomaterials.

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