Interdependence of intra- and inter-domain motions in the PSD-95 PDZ12 tandem

Abstract

PSD-95 is the most abundant scaffold protein in the postsynaptic density of neurons. Its two N-terminal PDZ domains form an autonomous structural unit and their interdomain orientation and dynamics was shown to be dependent on binding to various partner proteins. To understand the mechanistic details of the effect of ligand binding on interdomain structure and dynamics, we generated conformational ensembles using experimentally determined NOE interatomic distances and S 2 order parameters, available from the literature. In our approach no explicit restraints between the two domains were used and their fast dynamics was also treated independently. We found that intradomain structural changes induced by ligand binding have a profound effect on the interfaces where interdomain contacts can be formed, modulating the probability of the occurrence of specific domain-domain orientations. Our results suggest that the β2-β3 loop in the PDZ domains is a key regulatory region that, through interacting with the upstream residues of the C-terminal peptide ligand, influences both intradomain motions and supramodular rearrangement.