Effect of Polyphosphorylation on Behavior of Protein Disordered Regions

Abstract

Proteins interact with many charged biological macromolecules (polyelectrolytes), including inorganic polyphosphates. Recently a new protein post-translational modification, polyphosphorylation, or a covalent binding of polyphosphate chain to lysine, was demonstrated in human and yeast. Herein, we performed the first molecular modeling study of a possible effect of polyphosphorylation on behavior of the modified protein using replica exchange molecular dynamics simulations in atomistic force field with explicit water. Human endoplasmin (GRP-94), a member of heat shock protein 90 family, was selected as a model protein. Intrinsically disordered region in N-terminal domain serving as a charged linker between domains and containing a polyacidic serine and lysine-rich motif, was selected as a potent polyphosphorylation site according to literature data. Polyphosphorylation, depending on exact modification site, has been shown to influence on the disordered loop flexibility and induce its further expanding, as well as induce changes in interaction with ordered part of the molecule. As a result, polyphosphorylation in N-terminal domain might affect interaction of HSP90 with client proteins since these chaperones play a key role in protein folding.

Intrinsic disorder specifies discreet functions of nucleoplasmin-like histone chaperones

“…Regardless, it will now be important to learn how the addition of long polyphosphate chains to an already highly-charged and intrinsically disordered loop is harnessed to regulate protein function. A current computational analysis provides some insight: modeling the polyphosphorylation of the disordered linker region of Hsp70 impacts both the conformation ensemble of the IDR, and its interaction potency, implying that both inter- and intra-molecular interactions may change upon lysine polyphosphorylation 33 .…”

Intrinsic disorder of a nucleoplasmin‐like histone chaperone specifies its discrete nuclear and nucleolar functions

“…Regardless, it will now be important to learn how the addition of long polyphosphate chains to an already highly charged and intrinsically disordered loop is harnessed to regulate protein function. A current computational analysis provides some insight: modeling the polyphosphorylation of the disordered linker region of Hsp90 impacts both the conformation ensemble of the IDR, and its interaction potency, implying that both inter‐ and intramolecular interactions may change upon lysine polyphosphorylation [33].…”

New betulin imine derivatives with antioxidant and selective antitumor activity

“…34,35 It was envisaged that the imine bond plays a key role in the anticancer activity, due to the fact that its dynamic character favors the binding of amino acids which are essential for the growth of tumor cells. [36][37][38] Moreover, some studies indicated that the presence of hydroxyl units in the proximity of imine linkage improves the anticancer activity, by a synergistic antioxidant activity. 39,40 Bringing all this information together, the idea of binding betulin with imine units towards achieving new anticancer agents appears to be very promising.…”