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- W3132498851 abstract "Liquid-liquid phase separation (LLPS) is the mechanism underlying biomolecular condensate formation. Some intrinsically disordered protein regions can mediate homotypic phase separation but the underlying interactions are incompletely understood. To interrogate these interactions, we characterized the effects of residue type substitutions on phase behavior of the disordered low complexity domain of hnRNPA1 (A1-LCD). Using a stickers-and-spacers model where stickers are residues responsible for inter- and intra-molecular interactions while spacers contribute only minimally, we recently identified aromatic residues as the main stickers in the A1-LCD. We find a dual role for arginines as both auxiliary stickers and solvating spacers. Lysines weaken sticker-sticker interactions. Additionally, we found that net charge per residue (NCPR) modulates the solubility by three orders of magnitude. A strong charge bias decreases phase separation, while a small positive bias maximizes it. We sought to test these mean-field insights through NMR spectroscopy and pH titrations. NOEs of the WT light-phase confirm the spatial proximity between arginine and aromatic residues, consistent with aromatic-arginine interactions. Adding 19 additional charged residues, seven lysines and 12 aspartates, yields a construct with over twice the number of charged residues yet reduced NCPR. Chemical shifts indicate minimal perturbation of the conformational ensemble. Additionally, clusters of residues with enhanced relaxation rates were also consistent with those previously seen in WT, indicating that the aromatic residues remain the dominant stickers in the charged variants. pH dependency of the phase behavior confirmed that the driving force for phase separation is maximal at a slightly positive NCPR and indicate that the positive charge of lysines mediate their disruptive effects. These insights improve our understanding of how the driving force for phase separation is encoded in the sequence of intrinsically disordered proteins." @default.
- W3132498851 created "2021-03-01" @default.
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- W3132498851 date "2021-02-01" @default.
- W3132498851 modified "2023-10-16" @default.
- W3132498851 title "Exploring the Effects of Increased Charge Content on the Phase Behavior of a Protein Low Complexity Domain" @default.
- W3132498851 doi "https://doi.org/10.1016/j.bpj.2020.11.1962" @default.
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