1 research outputs found
Role of G326 in Determining the Aggregation Propensity of R3 Tau Repeat: Insights from Studies on R1R3 Tau Construct
The
Microtubule-binding repeat region (MTBR) of Tau has been studied
extensively due to its pathological implications in neurodegenerative
diseases like Alzheimer’s disease. The pathological property
of MTBR is mainly due to the R3 repeat’s high propensity for
self-aggregation, highlighting the critical molecular grammar of the
repeat. Utilizing the R1R3 construct (WT) and its G326E mutant (EE),
we determine the distinct characteristics of various peptide segments
that modulate the aggregation propensity of the R3 repeat using NMR
spectroscopy. Through time-dependent experiments, we have identified 317KVTSKCGS324 in R3 repeat as the aggregation initiating
motif (AIM) due to its role at the initial stages of aggregation.
The G326E mutation induces changes in conformation and dynamics at
the AIM, thereby effectively abrogating the aggregation propensity
of the R1R3 construct. We further corroborate our findings through
MD simulations and propose that AIM is a robust site of interest for
tauopathy drug design