Arginine π-stacking drives binding to fibrils of the Alzheimer protein Tau

Abstract

Aggregation of the Tau protein into fibrils defines progression of neurodegenerative diseases, including Alzheimer's Disease. The molecular basis for potentially toxic reactions of Tau aggregates is poorly understood. Here we show that π-stacking by Arginine side-chains drives protein binding to Tau fibrils. We mapped an aggregation-dependent interaction pattern of Tau. Fibrils recruit specifically aberrant interactors characterised by intrinsically disordered regions of atypical sequence features. Arginine residues are key to initiate these aberrant interactions. Crucial for scavenging is the guanidinium group of its side chain, not its charge, indicating a key role of π-stacking chemistry for driving aberrant fibril interactions. Remarkably, despite the non-hydrophobic interaction mode, the molecular chaperone Hsp90 can modulate aberrant fibril binding. Together, our data present a molecular mode of action for derailment of protein-protein interaction by neurotoxic fibrils.

Looking Beyond the Core: The Role of Flanking Regions in the Aggregation of Amyloidogenic Peptides and Proteins

“…Consequently, it is perhaps not surprising that fibrils with different structures may induce different effects in vivo. Ferrari et al (2020), for example, used a pull-down approach with FLAG-tagged Tau to show that different aggregation stages (monomer, oligomer, fibril) have altered reactivity with its cellular environment due to large conformational changes that occur when this natively unfolded protein self-assembles into a β-sheet rich fibrillary protein state. Given that the "fuzzy coat" of disordered peptide regions that flank the cores of amyloid fibrils can vary between fibril polymorphs (Gallardo et al, 2020b), the effect of these dynamic regions on the function, toxicity and further amplification of the fibrils themselves may also vary, perhaps rationalizing the epigenetic difference in disease development in individuals expressing the same aggregation-prone proteins.…”

Heterotypic interactions in amyloid function and disease

“…Moreover, BRCA1, a DNA nuclear protein, has been found to mis-localize and deposit with tau in different tauopathies, possibly causing loss of function and reducing DNA repair [56]. Furthermore, incubating different aggregated species of tau with rat brain lysate revealed a distinct interaction pattern compared to monomeric tau [57], suggesting that aggregate-specific interactions occur. Interestingly, interactions changed during the course of aggregation.…”

“…Early interactions contained proteins connected to Coat Protein I components, which in late stage aggregates were decreased in abundance [57]. In contrast, during these later stages of aggregation, proteins connected to RNA, phosphorylation and microtubules were able to interact highly with tau fibrils [57]. Co-immunoprecipitation of tau from microsomes isolated from AD and control brains showed that 42.9% of the proteins identified were only found in AD brains, with proteins involved in RNA translation having higher abundances [58].…”

Human Polymerase δ-Interacting Protein 2 (PolDIP2) Inhibits the Formation of Human Tau Oligomers and Fibrils

“…Polymerase δ-interacting protein 2 (PolDIP2, also known as PDIP38) has recently been identified as a specific binding partner of Tau monomers, but not Tau oligomers or fibrils [6]. PolDIP2 is a multi-functional protein originally described as a binding partner of the nuclear DNA polymerase Pol δ and proliferating cell nuclear antigen [7,8], but previous reports have suggested that PolDIP2 has also a regulatory role in cellular Tau aggregation [6,9]. The mechanism by which PolDIP2 regulates Tau aggregation remains to be addressed.…”