02380nas a2200265   4500008004100000022001400041245016600055210006900221260000900290300001400299490000700313520144700320653002801767653002501795653002901820653001301849653001401862653001101876100001701887700002201904700002201926700001601948700002401964856012601988       2024                        eng d  a1948-719300aDNA-mediated formation of phase-separated coacervates of the nucleic acid-binding domain of TAR DNA-binding protein (TDP-43) prevents its amyloid-like misfolding0 aDNAmediated formation of phaseseparated coacervates of the nucle  cOCT   a4105-41220 v153 a<p>
	Sequestration of protein molecules and nucleic acids to stress granules is one of the most promising strategies that cells employ to protect themselves from stress. In vitro, studies suggest that the nucleic acid-binding domain of TDP-43 (TDP-43tRRM) undergoes amyloid-like aggregation to beta-sheet-rich structures in low pH stress. In contrast, we observed that the TDP-43tRRM undergoes complex coacervation in the presence of ssDNA to a dense and light phase, preventing its amyloid-like aggregation. The soluble light phase consists of monomeric native-like TDP-43tRRM. The microscopic data suggest that the dense phase consists of spherical coacervates with limited internal dynamics. We performed multiparametric analysis by employing various biophysical techniques and found that complex coacervation depends on the concentration and ratio of the participating biomolecules and is driven by multivalent interactions. The modulation of these forces due to environmental conditions or disease mutations regulates the extent of coacervation, and the weakening of interactions between TDP-43tRRM and ssDNA leads to amyloid-like aggregation of TDP-43tRRM. Our results highlight a competition among the native state, amyloid-like aggregates, and complex coacervates tuned by various environmental factors. Together, our results illuminate an alternate function of TDP-43tRRM in response to pH stress in the presence of the ssDNA.</p>
10aamyloid-likeaggregation10acomplex coacervation10aDNA-protein interactions10aDynamics10apH stress10aTDP-431 aPatni, Divya1 aPatil, Anjali, D.1 aKirmire, Mona, S.1 aJha, Anjali1 aJha, Santosh, Kumar  uhttps://library.ncl.res.in/content/dna-mediated-formation-phase-separated-coacervates-nucleic-acid-binding-domain-tar-dna02594nas a2200229   4500008004100000022001400041245014700055210006900202260000800271300001400279490000700293520172200300653002902022653004402051653003302095653001802128100002402146700002202170700001602192700002402208856013202232       2026                        eng d  a1948-719300aStructural and mechanistic heterogeneity of the phase separation and aggregation of full-length TDP-43 is governed by environmental conditions0 aStructural and mechanistic heterogeneity of the phase separation  cAPR  a1362-13740 v173 a<p>
	TAR DNA-binding protein 43 (TDP-43) is an essential physiological protein implicated in several fatal neurodegenerative disorders. Interestingly, the nature of TDP-43 aggregates varies across patients and disease conditions, suggesting an underlying heterogeneity in its self-assembly behavior. In this study, we investigated two native-like states of full-length TDP-43: the native dimer (N form) and the native-like oligomer (O form). These are compact, folded states with similar secondary structures but differ in size. We found that the N and O forms respond differently to external perturbations and form distinct self-assemblies under stress conditions. Under electrostatic stress, both N and O forms undergo phase separation but produce condensates with markedly different morphologies and dynamics. The underlying mechanisms driving their phase separation are different. Under thermal stress, both forms convert into amyloid aggregates, but again with clearly different morphologies, biochemical properties, and aggregation pathways. These results demonstrate that multiple conformations of TDP-43 respond to distinct perturbations by assembling into structurally and mechanistically different higher-order assemblies. Our findings highlight how the interplay among the structural state, solvation environment, and self-assembly mechanism governs the heterogeneity of TDP-43 assemblies, offering new insights into their physiological roles and pathological relevance. This study suggests that the heterogeneity observed in patients associated with TDP-43 aggregation may arise from differences in the cellular stresses experienced by the protein and the corresponding assembly mechanisms engaged.</p>
10aAmyloid-like aggregation10amolecular mechanism of phase separation10anative-like phase separation10aSelf-assembly1 aDoke, Abhilasha, A.1 aKirmire, Mona, S.1 aJha, Anjali1 aJha, Santosh, Kumar  uhttps://library.ncl.res.in/content/structural-and-mechanistic-heterogeneity-phase-separation-and-aggregation-full-length-tdp-43