@article {49250,
	title = {Deciphering the monomeric and dimeric conformational landscapes of the full-length TDP-43 and the impact of the C-terminal domain},
	journal = {ACS Chemical Neuroscience},
	volume = {15},
	year = {2024},
	month = {NOV},
	pages = {4305-4321},
	type = {Article},
	abstract = {<p>
	The aberrant aggregation of TAR DNA-binding protein 43 kDa (TDP-43) in cells leads to the pathogenesis of multiple fatal neurodegenerative diseases. Decoding the proposed initial transition between its functional dimeric and aggregation-prone monomeric states can potentially design a viable therapeutic strategy, which is presently limited by the lack of structural detail of the full-length TDP-43. To achieve a complete understanding of such a delicate phase space, we employed a multiscale simulation approach that unearths numerous crucial features, broadly summarized in two categories: (1) state-independent features that involve inherent chain collapsibility, rugged polymorphic landscape dictated by the terminal domains, high beta-sheet propensity, structural integrity preserved by backbone-based intrachain hydrogen bonds and electrostatic forces, the prominence of the C-terminal domain in the intrachain cross-domain interfaces, and equal participation of hydrophobic and hydrophilic (charged and polar) residues in cross-domain interfaces; and (2) dimerization-modulated characteristics that encompass slower collapsing dynamics, restricted polymorphic landscape, the dominance of side chains in interchain hydrogen bonds, the appearance of the N-terminal domain in the dimer interface, and the prominence of hydrophilic (specifically polar) residues in interchain homo- and cross-domain interfaces. In our work, the ill-known C-terminal domain appears as the most crucial structure-dictating domain, which preferably populates a compact conformation with a high beta-sheet propensity in its isolated state stabilized by intrabackbone hydrogen bonds, and these signatures are comparatively faded in its integrated form. Validation of our simulated observables by a complementary spectroscopic approach on multiple counts ensures the robustness of the computationally predicted features of the TDP-43 aggregation landscape.</p>
},
	keywords = {chain collapsibility, domain-wisefluctuation, electrostatic dominance, hydrogen bond switchability, long-range crosstalk, persistent beta-character, protagonistic C-terminal domain, rugged phase space},
	issn = {1948-7193},
	doi = {10.1021/acschemneuro.4c00557},
	author = {Tammara, Vaishnavi and Doke, Abhilasha A. and Jha, Santosh Kumar and Das, Atanu}
}
