The expansion of homopolymeric glutamine (polyQ) or alanine (polyA) repeats in certain proteins owing to genetic mutations induces protein aggregation and toxicity, causing at least 18 human diseases. PolyQ and polyA repeats can also associate in the same proteins, but the general extent of their association in proteomes is unknown. Furthermore, the structural mechanisms by which their expansion causes disease are not well understood, and these repeats are generally thought to misfold upon expansion into aggregation-prone β-sheet structures like amyloids. However, recent evidence indicates a critical role for coiled-coil (CC) structures in triggering aggregation and toxicity of polyQ-expanded proteins, raising the possibility that polyA repeats may as well form these structures, by themselves or in association with polyQ. We found through bioinformatics screenings that polyA, polyQ and polyQA repeats have a phylogenetically graded association in human and non-human proteomes and associate/overlap with CC domains. Circular dichroism and cross-linking experiments revealed that polyA repeats can form—alone or with polyQ and polyQA—CC structures that increase in stability with polyA length, forming higher-order multimers and polymers in vitro. Using structure-guided mutagenesis, we studied the relevance of polyA CCs to the in vivo aggregation and toxicity of RUNX2—a polyQ/polyA protein associated with cleidocranial dysplasia upon polyA expansion—and found that the stability of its polyQ/polyA CC controls its aggregation, localization and toxicity. These findings indicate that, like polyQ, polyA repeats form CC structures that can trigger protein aggregation and toxicity upon expansion in human genetic diseases.
Thin sheets and small MoS 2 nanoparticles have been obtained by exfoliation/fragmentation processes via intense ultrasound cavitation in isopropyl alcohol (IPA). The formation mechanism, the structure (in terms of size, presence of defects, lattice periodicity) and the optical and vibrational properties of the obtained materials have been investigated by means of atomic force (AFM) and high-resolution transmission electron (HRTEM) microscopies and UV−visible near infrared (UV−vis−NIR) and diffuse reflectance infrared Fourier transform (DRIFT) spectroscopies. Fast-Fourier transform (FFT) analyses of HRTEM images have provided a simple and powerful tool to better evidentiate defective situations on extended and regular regions of exfoliated MoS 2 nanosheets with large lateral dimensions. The transparent ultracentrifuged portion of MoS 2 in IPA is characterized by size and height distributions peaking at about 6 and 1.5 nm, respectively, a fact which is indicative of very high fragmentation and very reduced stacking. The evolution of the UV−vis−NIR and DRIFT spectra upon increasing sonication time and ultracentrifugation give unprecedented information on the optical properties of nanoparticles, on the vibrational properties of surface species, and on the lattice modes of virgin and fragmented material. It is also demonstrated that the extensive layer fragmentation due to the cavitation field is associated with rupture of MoSMo bonds and subsequent exposure of coordinatively and chemically unsaturated Mo and S species. These chemically unsaturated species readily react with the IPA solvent and with atmospheric oxygen with the predominant formation of surface hydroxyl, alkyl, and, to a lesser extent, oxidized species like sulfate and carbonylic and carboxylate groups. Hence, it is concluded that the edges formed by layers breaking in the IPA solution are fully functionalized. This spectroscopic study is made possible by the complete absence of adsorbed IPA, which being a low boiling solvent can be easily removed from MoS 2 and does not interfere in the DRIFT measurements. The transparent fraction containing the fragmented particles can be used for blending MoS 2 nanoparticles with high surface area materials. This process is favored by the volatile character of IPA, which can be easily removed from the ultrasonicated material. This makes the proposed method fully suitable to prepare MoS 2 -based hybrid composite materials by simple impregnation of high surface area supports.
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