Interaction and structural modification of topoisomerase IIalpha by peptidyl prolyl isomerase, pin1: an in silico study.

The peptidyl prolyl isomerase (Pin1) that catalyzes the isomerization of peptide bonds involving proline and phosphorylated serine/threonine/tyrosine and alters the conformation and differential folding has been implicated in the regulation and function of phosphorylated proteins including mitotic and cell cycle proteins viz. Cdc25c, Bcl2, p53 etc. DNA topoisomerase IIalpha is one of the nuclear enzymes that maintain the DNA topology and regulates nuclear transactions like chromatin segregation and mitosis. In the present studies, we have carried out in-silico investigations on the possibilities of pin1 interaction with topo IIalpha and its functional regulation. We found ten potential pin1 interacting sites within topo IIalpha, which were part of loop and/or low complexity regions except helix at S802 within the catalytic domain. Proline directed phosphorylation was found to be possible at 1354, 1361, 1393 positions by cdk. Change in dihedral angle (omega) to 0 degree at all potential pin1 interacting sites at 575, 602, 802 and 950 for cis conformation of peptide bond introduced significant structural change with higher potential energy. All-cis-topo IIalpha structure reveals that potential pin1 sites come closer to each other, perhaps forming a motif, thereby suggesting cooperative phenomenon to maintain higher potential energy conformation. The bio-informatic analysis of topo IIalpha showed that multisite interaction of pin1 is possible at all the predicted sites. However, a strong possibility of pin1 interaction exist within c-terminal at 1213, 1247, 1354, 1361, 1393 sites, which may lead to either alterations in localization or modification in the activity and perhaps stability of the enzyme.