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Protein structure in reversible amyloid formed by low-complexity regions


There is a current renaissance of research on membraneless organelles and their relationship to life in the cell. Protein-protein interactions between mysterious regions of proteins called Low Complexity Regions (LCRs) are known to be important for organizing these membraneless organelles. Membraneless organelles include: P-bodies, involved in mRNA degradation; the nucleolus, the center of rRNA genesis; Cajal bodies, related to telomerase function; and Stress Granules (SGs), dynamic organelles that form and disappear in response to stressful stimuli. LCRs from SG proteins form labile hydrogels composed of amyloid-like fibrils that are associated with organization of SGs. To elucidate the organization of these complexes we determined atomic resolution structures of adhesive five segments within LCRs. The resulting structures resemble known amyloid structures because the crystalized segments formed pairs of mating β-sheets that ran along a fibril axis. However, these five structures are distinct from known amyloid because of sharp kinks in the peptide backbones of the mating β-sheets. In conjunction with the relatively hydrophilic nature of these segments, the fibrils they form are labile; a departure from the stability associated with disease related amyloid. We termed this new type of structure low-complexity aromatic rich kinked segments (LARKS) and found their properties to be consistent with in vitro and cellular behavior needed to form dynamic membraneless assemblies found in the cell. A computational method, 3-D profiling, predicts that some 1725 proteins in the human proteome have two or more LARKS in LCRs that are consistent with properties needed to form membraneless assemblies.

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