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4. Liquid–liquid phase separation of alpha‐synuclein increases the structural variability of fibrils formed during amyloid aggregation.

Author

Ziaunys, Mantas, Sulskis, Darius, Veiveris, Dominykas, Kopustas, Aurimas, Snieckute, Ruta, Mikalauskaite, Kamile, Sakalauskas, Andrius, Tutkus, Marijonas, and Smirnovas, Vytautas

Abstract

Protein liquid–liquid phase separation (LLPS) is a rapidly emerging field of study on biomolecular condensate formation. In recent years, this phenomenon has been implicated in the process of amyloid fibril formation, serving as an intermediate step between the native protein transition into their aggregated state. The formation of fibrils via LLPS has been demonstrated for a number of proteins related to neurodegenerative disorders, as well as other amyloidoses. Despite the surge in amyloid‐related LLPS studies, the influence of protein condensate formation on the end‐point fibril characteristics is still far from fully understood. In this work, we compare alpha‐synuclein aggregation under different conditions, which promote or negate its LLPS and examine the differences between the formed aggregates. We show that alpha‐synuclein phase separation generates a wide variety of assemblies with distinct secondary structures and morphologies. The LLPS‐induced structures also possess higher levels of toxicity to cells, indicating that biomolecular condensate formation may be a critical step in the appearance of disease‐related fibril variants. [ABSTRACT FROM AUTHOR]

Published
2024
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7. Finke-Watzky Two-Step Nucleation-Autocatalysis Model of S100A9 Amyloid Formation : Protein Misfolding as 'Nucleation' Event

Author

Iashchishyn, Igor A., Sulskis, Darius, Ngoc, Mai Nguyen, Smirnovas, Vytautas, Morozova-Roche, Ludmilla A., Iashchishyn, Igor A., Sulskis, Darius, Ngoc, Mai Nguyen, Smirnovas, Vytautas, and Morozova-Roche, Ludmilla A.

Abstract

Quantitative kinetic analysis is critical for understanding amyloid mechanisms. Here we demonstrate the application of generic Finke-Watzky (F-W) two-step nucleation-autocatalytic growth model to the concentration-dependent amyloid kinetics of proinflammatory alpha-helical S100A9 protein at pH 7.4 and at 37 and 42 degrees C. The model is based on two pseudoelementary reaction steps applied without further analytical constraints, and its treatment of S100A9 amyloid self-assembly demonstrates that initial misfolding and beta-sheet formation, defined as "nucleation" step, spontaneously takes place within individual S100A9 molecules at higher rate than the subsequent fibrillar growth. The latter, described as an autocatalytic process, will proceed if misfolded amyloid-prone S100A9 is populated on a macroscopic time scale. Short lengths of S100A9 fibrils are consistent with the F-W model. The analysis of fibrillar length distribution by the Beker-Doring model demonstrates independently that such distribution is solely determined by slow fibril growth and there is no fragmentation or secondary pathways decreasing fibrillar length.

Published
2017
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