Loss of intramolecular electrostatic interactions and limited conformational ensemble may promote self‐association of cis–tau peptide. Issue 3 (21st January 2015)

• Record Type: Journal Article
• Authors: Barman, Arghya; Hamelberg, Donald
• Is Part Of: Proteins. Volume 83:Issue 3(2015)
• Page Start: 436
• Page End: 444
• Publication Date: 2015-01-21
• Subjects: Proteins -- Periodicals; Proteins -- Periodicals; 572.6
• DOI: 10.1002/prot.24740
• Languages: English
• ISSNs: 0887-3585

Abstract

<abstract abstract-type="main"> <title>ABSTRACT</title> <p>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 <italic>cis</italic> peptidyl prolyl conformation of a phosphorylated threonine‐proline motif in the tau protein renders tau more prone to aggregation than the <italic>trans</italic> isomer. However, little is known about the role of peptidyl prolyl <italic>cis/trans</italic> isomerization in tau aggregation. Here, we show that intra‐molecular electrostatic interactions are better formed in the <italic>trans</italic> isomer. We explore the conformational landscape of the tau segment containing the phosphorylated‐Thr<sup>231</sup>‐Pro<sup>232</sup> 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 <italic>cis</italic> 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. Proteins 2015; 83:436–444. © 2014 Wiley Periodicals, Inc.</p> </abstract>