02235nas a2200217   4500008004100000022001400041245012000055210006900175260000900244300001100253490000900264520144800273653002901721653002501750653003401775653001101809653002801820100001701848700002401865856012801889       2023                        eng d  a1570-963900aThermodynamic modulation of folding and aggregation energy landscape by DNA binding of functional domains of TDP-430 aThermodynamic modulation of folding and aggregation energy lands  cJUL   a1409160 v18713 a<p>
	TDP-43 is a vital nucleic acid binding protein which forms stress-induced aberrant aggregates in around 97% cases of ALS, a fatal neurodegenerative disease. The functional tandem RRM domain of the protein (TDP-43tRRM) has been shown to undergo amyloid-like aggregation under stress in a pH-dependent fashion. However, the underlying thermodynamic and molecular basis of aggregation and how the energy landscape of folding, stability, and aggregation are coupled and modulated by nucleic acid binding is poorly understood. Here, we show that the pH stress thermodynamically destabilizes the native protein and systematically populates the unfoldedlike aggregation-prone molecules which leads to amyloid-like aggregation. We observed that specific DNA binding inhibits aggregation and populates native-like compact monomeric state even under low-pH stress as measured by circular dichroism, ANS binding, size exclusion chromatography, and transmission electron microscopy. We show that DNA-binding thermodynamically stabilizes and populates the native state even under stress and reduces the population of unfolded-like aggregation-prone molecules which leads to systematic aggregation inhibition. Our results suggest that thermodynamic modulation of the folding and aggregation energy landscape by nucleic-acid-like molecules could be a promising approach for effective therapeutic intervention in TDP-43-associated proteinopathies.</p>
10aAmyloid-like aggregation10aNucleic acid binding10aRNA recognition motifs (RRMs)10aTDP-4310aThermodynamic stability1 aPatni, Divya1 aJha, Santosh, Kumar  uhttps://library.ncl.res.in/content/thermodynamic-modulation-folding-and-aggregation-energy-landscape-dna-binding-functional02594nas 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