The structure of the unstructured: mosaic of tau protein linear motifs obtained by high-resolution techniques and molecular simulation

Abstract

Intrinsically disordered proteins are flexible molecules with important physiological functions. Their mode of action often involves short segments, called linear motifs, which may exhibit distinct structural propensities. Tau is intrinsically disordered, microtubule-associated protein involved in the pathogenesis of various tauopathies. In this review we analyze the collection of 3D structures of tau local linear motifs gained from the deposited structures of tau complexes with various binding partners as well as of tau-tau complexes; determined by X-ray and electron crystallography, single-particle electron microscopy, NMR spectroscopy and molecular dynamics simulations. Insights into the partially stabilized conformations of tau linear motifs are valuable for understanding the physiological and pathological processes involving tau protein.

Hyperphosphorylated Tau Inflicts Intracellular Stress Responses that Are Mitigated by Apomorphine

“…Multiple TEM observations of separate batches of p-tau consistently showed this trend with few, if any, PHF-like fibrils. These results were consistent with the fact that tau is an intrinsically disordered protein that may progress through different structural propensities[ 81 ] before forming the final species of PHFs and NFTs. It is possible that a portion of p-tau molecules were irreversibly trapped as amorphous deposits in vitro and in vivo [ 82 ].…”

Recent Advances in Our Molecular and Mechanistic Understanding of Misfolded Cellular Proteins in Alzheimer’s Disease (AD) and Prion Disease (PrD)

“…Neuron-abundant ~352 to ~441 amino acid microtubule-associated protein tau proteins (MAPT; chr 17q21.31; https://www.genecards.org/cgi-bin/carddisp.pl?gene=MAPT; last accessed 18 January 2022) are normally involved in the organization and stabilization of the internal microtubule system of cells of the human CNS. Recently described as 'intrinsically disordered', MAPT proteins are centrally involved in homeostasis, the maintenance of neuronal cytoarchitecture, three-dimensional neuronal shape and overall synaptic organization [30][31][32]. Interestingly MAPT gene transcripts in the human brain and CNS undergo alternative splicing from a single gene to yield six different tau protein isoforms that are expressed at different ratios in neurodegeneration, which result in tau pathology of paired-helical filaments, neurofibrillary tangles, and tau fibrillar aggregates with detrimental effects such as microtubule destabilization [16,33].…”

The relationship between protein modified folding molecular network and Alzheimer’s disease pathogenesis based on BAG2-HSC70-STUB1-MAPT expression patterns analysis

“…Its function is to stabilize axon microtubules, and phosphorylation can reduce its ability to bind microtubules (Laurent and Blum, 2018). Native Tau is disordered and needs to be folded into a suitable motif to perform its function (Cehlar et al, 2021). Protein folding is a complicated process that involves correctly folding and stabilizing amino acid chains into functional proteins (Heneka et al, 2015).…”

“…Specific branch research directions include hyperphosphorylation Tau (Silvestro et al, 2022), phosphoryd plasma Tau (Pilotto et al, 2022), abnormal aggregation of Tau (Gao et al, 2018), regulation of iron accumulation Tau (Rao and Adlard, 2018) and truncation Tau (Quintanilla et al, 2020). The exact mechanism of Tau leading to NFT is still controversial, but researchers cannot deny that the degradation and folding of Tau is the key point of this hypothesis (Laurent and Blum, 2018;Cehlar et al, 2021;Sallaberry et al, 2021). However, the relationship between proteinmodified folding molecular networks and AD pathogenesis is complex and multifaceted (Rutledge et al, 2022).…”