Loss of intramolecular electrostatic interactions and limited conformational ensemble may promote self-association ofcis-tau peptide

Abstract

Self-association of proteins can be triggered by a change in the distribution of the conformational ensemble. Posttranslational modification, such as phosphorylation, can induce a shift in the ensemble of conformations. In the brain of Alzheimer's disease patients, the formation of intra-cellular neurofibrillary tangles deposition is a result of self-aggregation of hyper-phosphorylated tau protein. Biochemical and NMR studies suggest that the cis peptidyl prolyl conformation of a phosphorylated threonine-proline motif in the tau protein renders tau more prone to aggregation than the trans isomer. However, little is known about the role of peptidyl prolyl cis/trans isomerization in tau aggregation. Here, we show that intra-molecular electrostatic interactions are better formed in the trans isomer. We explore the conformational landscape of the tau segment containing the phosphorylated-Thr(231)-Pro(232) motif using accelerated molecular dynamics and show that intra-molecular electrostatic interactions are coupled to the isomeric state of the peptidyl prolyl bond. Our results suggest that the loss of intra-molecular interactions and the more restricted conformational ensemble of the cis isomer could favor self-aggregation. The results are consistent with experiments, providing valuable complementary atomistic insights and a hypothetical model for isomer specific aggregation of the tau protein.

Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

“…Accelerated MD were used to explore the conformational landscape of the tau segment containing the phosphorylated-Thr(231)-Pro(232) motif. 531 The results show that intramolecular electrostatic interactions are coupled to the isomeric state of the peptidyl prolyl bond. Intramolecular electrostatic interactions are better formed in the trans isomer; however, the loss of intramolecular interactions and the more restricted conformational ensemble of the cis isomer could favor self-aggregation.…”

“…Accelerated MD were used to explore the conformational landscape of the tau segment containing the phosphorylated-Thr( 231)-Pro(232) motif. 531 The results…”

“…It could be possible that both trans-tau and cis-tau are able to aggregate, depends in the environment in the experimental conditions to change their energy landscape. Accelerated MD were used to explore the conformational landscape of the tau segment containing the phosphorylated-Thr(231)-Pro(232) motif . The results show that intramolecular electrostatic interactions are coupled to the isomeric state of the peptidyl prolyl bond.…”

“…Two independent simulations found that the effect of phosphorylation on proline-rich domains of tau is mostly electrostatic. 520,531 Lyons et al modeled the phosphorylation induced conformational change on a peptide of htau225-250 with different phosphorylation patterns of the peptide (pThr231 and/or pSer235). All patterns were found to disrupt a nascent terminal β-sheet pattern ( 226 VAVVR 230 and 244 QTAPVP 249 ).…”

Apolipoprotein E isoforms differentially regulate matrix metallopeptidase 9 function in Alzheimer’s disease

“…aberrant activity of tau in AD is instead deemed to be resultant of its post-translational modifications, specifically the changes in the tau phosphorylation pattern [80]. This phosphorylation at specific phospho-sites modifies the conformation of tau, promoting aggregation into an insoluble form, also known as paired helical filaments [72], [81], [82].…”