Biology subjects

Sarkany, Z.

Publications and source records attributed to Sarkany, Z..

3 recordsLinked to original sources

bioRxiv2022

Drug repurposing of dopaminergic drugs to inhibit Ataxin-3 aggregation

The accumulation of mutant ataxin-3 (Atx3) in neuronal nuclear inclusions is a pathological hallmark of Machado-Joseph disease (MJD), also known as Spinocerebellar Ataxia Type 3. Decreasing the protein aggregation burden is a possible disease-modifying strategy to tackle MJD and other neurodegenerative disorders for which only symptomatic treatments are currently available. We performed a drug repurposing screening to identify inhibitors of Atx3 aggregation with known toxicological and pharmacokinetic profiles. Interestingly, dopamine hydrochloride and other catecholamines are among the most potent inhibitors of Atx3 aggregation in vitro. Our results indicate that low micromolar concentrations of dopamine markedly delay the formation of mature amyloid fibrils of mutant Atx3 through the inhibition of the earlier oligomerization steps. Although dopamine itself does not pass the blood-brain barrier, dopamine levels in the brain can be increased by low doses of dopamine precursors and dopamine agonists commonly used to treat Parkinsonian symptoms. These findings disclose a possible application of dopaminergic drugs to halt or reduce Atx3 accumulation in the brains of MJD patients.

neuroscience↗

bioRxiv2022

Quantification of surface tension effects and nucleation-and-growth rates during self-assembly of biological condensates

Liquid-solid and liquid-liquid phase separation (PS) drives the formation of functional and disease-associated biological assemblies. Principles of phase equilibrium are here employed to derive a general kinetic solution that predicts the evolution of the mass and size of biological assemblies. Thermodynamically, protein PS is determined by two measurable concentration limits: the saturation concentration and the critical solubility. Due to surface tension effects, the critical solubility can be higher than the saturation concentration for small, curved nuclei. Kinetically, PS is characterized by the primary nucleation rate constant and a combined rate constant accounting for growth and secondary nucleation. It is demonstrated that the formation of a few number of large condensates is possible without active mechanisms of size control and in the absence of coalescence phenomena. Our exact analytical solution can be used to interrogate how the elementary steps of PS are affected by candidate drugs.

biophysics↗

bioRxiv2022

Pathogen-specific structural features of two key players in Candida albicans morphogenetic switch

Ras-like protein 1 (CaRas1) is a key regulator of the switch between the yeast and hyphal forms of Candida albicans, a feature associated with pathogenesis. CaRas1 is activated by the guanine nucleotide exchange factor (GEF) CaCdc25, triggering hyphal growth-related signaling pathways through its highly conserved GTP-binding domain (G-domain). An important function in hyphal growth has also been proposed for the long hypervariable region downstream of the G-domain of CaRas1, whose unusual content of polyQ stretches and Q/N repeats make CaRas1 unique within Ras-family proteins. Despite its biological importance, both the structure of CaRas1 and the molecular basis of its activation by CaCdc25 remain unexplored. Here, we show that CaRas1 displays an elongated shape and that its hypervariable region contains helical structural elements with intramolecular coiled-coil propensity and limited conformational flexibility. Functional assays revealed that CaRas1 activation by CaCdc25 is highly efficient, with 5-to 2000-fold higher activity levels than reported for human GEFs. In addition, the threedimensional structure of the catalytic region of CaCdc25, together with the structural characterization of CaRas1/CaCdc25 complexes, unveiled a specific region located in the -helical hairpin of CaCdc25, critical for CaRas1 activation, where negatively charged substitutions reduce its activity. The unique structural features of the low complexity region of CaRas1 and the distinctive properties of CaRas1 activation by CaCdc25, common in the homologous proteins from CTG-clade species, uncover novel strategies to target key virulence factors in human-infecting fungal pathogens.

biochemistry↗