Abstract
Tau is a microtubule-associated protein that promotes microtubule assembly and stability. This protein is implicated in several neurodegenerative diseases, including Alzheimer’s. To date, the three-dimensional (3D) structure of tau has not been fully solved, experimentally. Even the most recent information is sometimes controversial in regard to how this protein folds, interacts, and behaves. Predicting the tau structure and its profile sheds light on the knowledge about its properties and biological function, such as the binding to microtubules (MT) and, for instance, the effect on ionic conductivity. Our findings on the tau structure suggest a disordered protein, with discrete portions of well-defined secondary structure, mostly at the microtubule binding region. In addition, the first molecular dynamics simulation of full-length tau along with an MT section was performed, unveiling tau structure when associated with MT and interaction sites. Electrostatics and conductivity were also examined to understand how tau affects the ions in the intracellular fluid environment. Our results bring a new insight into tau and tubulin MT proteins, their characteristics, and the structure–function relationship.
Highlights
This extended form is important to the tau function, as it allows a proper exposure, flexibility, and contact of the MTBR residues with tubulin MT [48]
Our findings indicate that tau in its dephosphorylated form maintains the normal K+ diffusion and discreetly increases Na+ diffusion, which, must be more available to leave the inside of the neuron
The prediction of a tau 3D structure leads to a model that was equilibrated in solution—intracellular ionic fluid—and associated with an MT wall
Summary
Tau is an intrinsically disordered protein (IDP) that stabilizes and promotes the assembly of micTroautubisualens i(nMtrTins)siincanlleyurdoinsosr(dFeigreudrep1r)o; tiet iins, (thIDerPe)fothrea,tasmtaibcirloiztuesbualned-apssroocmiaotetedsptrhoeteaisnse(MmAblPy) o[1f]. NScttirounct[u4r].ally, tau is considered as a spacer between adjacent MTs, that is not its main function [4]. The adult largest tau isoform has 441 amino acids, comprising a projection domain with two aminToh-eteardmuinltallaringseesrttstauN,iseonfocormdedhabsy44e1xoanmsin2oaancdid3s,, caopmrpolriinsien-rgicahprreogjeiocntioannddotmheaimn iwcriothtutbwuole abminindoin-tgerrmeginioanl in(MseTrtBsRN),, ewnictohdfeodubr yimexpoenrfse2ctanredp3e,aatsp(rFoilginuer-eri2ch). Besides the relevant structural support function, that comes from the interaction between tau and the tuBbeusliidneMs Tths,etareulepvlaaynst asntruimctpuorartlasnutproploeritnfunnercvtioouns, sthysattecmomdiesseafsreosm. Osphorylation, glycosylation, nitratSioenv,egralyl captioosnt-,turabniqsulaittiionnaatilonm, aomdoifnicgatoiothnesrs c[1a3n,14o].ccTuhre diengretaeuo,f thneasmeemlyo,dipfihcaotsipohnosriyslwathioant, wgillylcleoasdyltaotiaonn,ornmitarlaotiropna,thgolylocgaitciaolnf,unucbtiiqouniintign.aItniopna, rtaimcuolanrg, taouthpehrossp[1h3o,r1y4l]a.tioTnheis tdheegmreoestosftutdhieedse modifications is what will lead to a normal or pathological functioning. Tau Biomolecules 2019, 9, 116 alteration, as it is established that the abnormal hyperphosphorylation is associated with AD [15,16], a dementia that currently has no cure
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