Edited by Wilhelm JustProteins may undergo adaptive structural transitions to accommodate to their cellular milieu and respond to external signals. Modulation of conformational ensembles can rewire the intra-or intermolecular interaction networks and shift between different functional states. Adaptive conformational transitions are associated with protein fuzziness, which enables (a) rewiring interaction networks via alternative motifs, (b) new functional features via allosteric motifs, (c) functional switches upon post-translational modifications, or (d) regulation of higher-order organizations. We propose that all these contextdependent functional changes are intertwined with structural multiplicity or dynamic disorder in protein assemblies and can only be described by stochastic structure-function relationships.
Motif-mimicry is exploited by viruses to interfere with host regulatory networks and has also been suggested as a prevalent strategy for eukaryotic and prokaryotic pathogens. Using the same peptide motif however does not guarantee more effective interactions with the host. Motif-mediated interactions require a flexible or disordered environment, with structural and dynamic features that should differ between the competing host and viral proteins. Using the eukaryotic linear motif (ELM) database we analyzed the protein regions which contained the eukaryotic and viral motifs, including human and human virus ELMs with common target sites. We found that although the eukaryotic motifs are associated with a lack of structure, they are more stable than their flanking regions and can serve as molecular recognition elements. In contrast, eukaryotic viral motifs are often located in more ordered regions, but have increased local flexibility or disorder compared to their embedding environment. Most viral ELMs are devoid of stable binding elements and remain fuzzy after binding. Fuzziness reduces the entropic cost of binding and imparts versatile interaction modes to increase binding promiscuity and to compete with multiple host peptides. Fuzzy interactions confer further functional benefits such as the combinatorial usage of motifs, and a fine-tuning affinity via post-translational modifications.
Protein 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 amyloidlike 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 be applicable to screen for pathological effects of mutations. FG FG FGFS N/Q FG RG N/Q RG N/Q FG FG FGFS FG RG N/Q RG N/Q FG FG FGFS N/Q FG RG N/Q RG FGFS FG FG FG Q/N Q/N
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