02962nas a2200277   4500008004100000022001400041245013400055210006900189260000800258300001400266490000700280520195400287653002502241653002702266653002802293653003202321653002502353653003002378653003602408653002302444100002302467700002402490700002402514700001502538856013102553       2024                        eng d  a1948-719300aDeciphering the monomeric and dimeric conformational landscapes of the full-length TDP-43 and the impact of the C-terminal domain0 aDeciphering the monomeric and dimeric conformational landscapes   cNOV  a4305-43210 v153 a<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>
10achain collapsibility10adomain-wisefluctuation10aelectrostatic dominance10ahydrogen bond switchability10along-range crosstalk10apersistent beta-character10aprotagonistic C-terminal domain10arugged phase space1 aTammara, Vaishnavi1 aDoke, Abhilasha, A.1 aJha, Santosh, Kumar1 aDas, Atanu  uhttps://library.ncl.res.in/content/deciphering-monomeric-and-dimeric-conformational-landscapes-full-length-tdp-43-and-impact-c02896nas a2200229   4500008004100000022001400041245011200055210006900167260000900236300001400245490000700259520209400266653001102360653001702371653003402388653001302422653003002435653003502465100002302500700001502523856012802538       2025                        eng d  a1948-719300aDecoding the relationship between alzheimer's disease and type-2 diabetes via the protein aggregation prism0 aDecoding the relationship between alzheimers disease and type2 d  cAUG   a3003-30190 v163 a<p>
	Alzheimer's disease (AD) and type-2 diabetes (T2D) are two fatal human diseases and have been linked to the aberrant aggregation of two distinct peptides, amyloid-beta (A beta) and human islet amyloid polypeptide (hIAPP), respectively. These two peptide aggregates, even with distal deposition sites (brain and pancreas), act as mutual beneficiaries. We here unveiled the crosstalk in a self-consistent fashion using atomistic simulations by comparing the kinetics and thermodynamics of self- and cross-aggregations of A beta(42) and hIAPP and their modulations by preformed fibrillar templates. Templates (specifically hIAPP) generally accelerate aggregation, alter the relative order of aggregation rates (cross-aggregation &gt; A beta self-aggregation &gt; hIAPP self-aggregation for nontemplated and hIAPP self-aggregation &gt; cross-aggregation &gt; A beta self-aggregation for templated), and flip the mutual impact (hIAPP aggravates A beta aggregation in nontemplated and the reverse in templated). Higher instances of breaking larger aggregates and longer residence times of smaller aggregates decelerate aggregation, whereas interpeptide electrostatics (universal) and hydrogen bonds (templated) assist it. However, the equilibrium aggregability pattern contradicts kinetic rank-ordering, as A beta displays a higher aggregability than hIAPP, templates increase aggregability for both peptides, and A beta's self-aggregability supersedes cross-aggregability, which further surpasses hIAPP's self-aggregability. The equilibrium ensembles encompass polymorphic, nonfibrillar oligomers having substantially reduced alpha-helicity and slight beta-propensity, with both parallel and antiparallel interpeptide orientations, primarily stabilized by electrostatics. A higher equilibrium aggregability means a greater helix-breaking capacity, a bias toward parallel orientation, and a lesser structural polymorphism. Water expulsion from peptide surroundings and distortion of water tetrahedrality prove that aggregation follows the liquid-liquid phase separation (LLPS) model.</p>
10aamylin10aAmyloid-beta10aliquid-liquidphase separation10aOligomer10aself vs cross-aggregation10aunseeded vs seeded aggregation1 aTammara, Vaishnavi1 aDas, Atanu  uhttps://library.ncl.res.in/content/decoding-relationship-between-alzheimers-disease-and-type-2-diabetes-protein-aggregation