Cooperative Fluctuations Point to the Dimerization Interface of P53 Core Domain

Abstract

Elastic network models are used for investigation of the p53 core domain functional dynamics. Global modes of motion indicate high positive correlations for residue fluctuations across the A-B interface, which are not observed at the B-C interface. Major hinge formation is observed at the A-B interface upon dimerization indicating stability of the A-B dimer. These findings imply A-B as the native dimerization interface, whereas B-C is the crystal interface. The A-B dimer exhibits an opening-closing motion about DNA, supporting the previously suggested clamp-like model of nonspecific DNA binding followed by diffusion. Monomer A has limited positive correlations with DNA, while monomer B exhibits high positive correlations with DNA in the functionally significant slow modes. Thus, monomer B might seem to maintain the stability of the dimer-DNA complex by forming the relatively fixed arm of the dimer clamp, whereas the other arm of the clamp, monomer A, might allow sliding via continuous association/dissociation mechanisms.

Probing potential binding modes of the p53 tetramer to DNA based on the symmetries encoded in p53 response elements

“…While it was suspected that the AB dimer in the trimeric p53–DNA structure ( 8 ) may be caused by crystal packing, it is also possible that the AB dimer has biological significance ( 11 , 26 , 27 ). Here we make use of this structure in building possible binding modes, to see how its assemblies can fit different sequence and geometry patterns to allow one quarter-site to interact with p53 specifically (chain B) and the second to have a lesser contact (chain A).…”

Comparative Study of Elastic Network Model and Protein Contact Network for Protein Complexes: The Hemoglobin Case

“…Both GNM and ANM have been used to investigate protein-protein interfaces. Kantarci et al [ 66 ] firstly applied GNM to classify interfaces of p53 core domain into the dimerization interface and crystal interface on the base of interfacial dynamics. Zen et al [ 67 ] extended this method to study the interface of 22 representative dimers.…”

The elastic network model reveals a consistent picture on intrinsic functional dynamics of type II restriction endonucleases

“…In elastic network models, the residues with high mean square fluctuations in the highest frequency modes are termed as hot spot residues . Although these residues constitute a small fraction of the protein structure, they are critical for the binding and stability of the protein and are highly correlated with conserved residues (Isin et al 2002, Keskin et al 2004, Haliloglu et al 2005, Kantarci et al 2006.…”