Terminal Capping of Amyloidogenic Tau Fragments Modulates their Fibrillation Propensity

Abstract

The aberrant folding of proteins leading to the formation of characteristic cross-β-sheet rich amyloid structures is implicated in the pathogenesis of a variety of debilitating diseases. In many cases, often depending upon amino acid composition, only a small segment of a large protein participates in amyloid core formation and is in fact capable of self-assembling into amyloid, independent of the rest of the protein. Therefore, such peptide fragments serve as useful model systems for protein aggregation studies. An important factor that has often been underestimated while using peptides to mimic full length protein, is the charge on the peptide termini. We have investigated the effect of the termini on aggregation of amyloidogenic peptides from microtubule associated intrinsically disordered protein Tau, implicated in Alzheimer's disease (AD) and Tauopathies. Unlike other amyloidogenic proteins, Tau is highly soluble and does not readily aggregate without anionic co-factors, such as heparin. Our experiments show that modification of the termini can drastically modulate the fibrillation of hexapeptide from repeat 3 (R3)-paired helical filament 6 (PHF6) and full length R3 of Tau, both with and without heparin. We found that even without heparin, PHF6 and R3 peptides that were capped at both the termini readily formed amyloid fibrils. In presence of heparin, only PHF6 with free termini and PHF6 with free N-terminus were unable to form fibrils. Our molecular dynamics simulations on PHF6 capping variants agree well with our experiments and provide insights into how terminal capping affects the self-assembly process. In addition to the effect of terminal capping on Tau fibrillation, we are also studying cross-interactions between peptides associated with AD and Type-2-diabetes, in order to understand the underlying link between these highly prevalent diseases. I will discuss some of our recent results from these studies.