Altered dynamics may drift pathological fibrillization in membraneless organelles

Publication date: Available online 16 April 2019Source: Biochimica et Biophysica Acta (BBA) - Proteins and ProteomicsAuthor(s): B. Tüű-Szabó, G. Hoffka, N. Duro, M. FuxreiterAbstractProtein phase transition can generate non-membrane bound cellular compartments, which can convert from liquid-like to solid-like states. While the molecular driving forces of phase separation have been largely understood, much less is known about the mechanisms of material-state conversion. We apply a recently developed algorithm to describe the weak interaction network of multivalent motifs, and simulate the effect of pathological mutations. We demonstrate that linker dynamics is critical to the material-state of biomolecular condensates. We show that linker flexibility/mobility is a major regulator of the weak, heterogeneous meshwork of multivalent motifs, which promotes phase transition and maintains a liquid-like state. Decreasing linker dynamics increases the propensity of amyloid-like fragments via hampering the motif-exchange and reorganization of the weak interaction network. In contrast, increasing linker mobility may compensate rigidifying mutations, suggesting that the meshwork of weak, variable interactions may provide a rescue mechanism from aggregation. Motif affinity, on the other hand, has a moderate impact on fibrillization. Here we demonstrate that the fuzzy framework provides an efficient approach to handle the intricate organization of membraneless organelles, and could also...

Source: Biochimica et Biophysica Acta (BBA) Proteins and Proteomics - April 17, 2019 Category: Biochemistry Source Type: research