posted on 2021-02-16, 14:03authored byJacques Kumutima, Xin-Qiu Yao, Donald Hamelberg
The multifunctional protein p53 is
the central molecular sensor
of cellular stresses. The canonical function of p53 is to transcriptionally
activate target genes in response to, for example, DNA damage that
may trigger apoptosis. Recently, p53 was also found to play a role
in the regulation of necrosis, another type of cell death featured
by the mitochondrial permeability transition (mPT). In this process,
p53 directly interacts with the mPT regulator cyclophilin D, the detailed
mechanism of which however remains poorly understood. Here, we report
a comprehensive computational investigation of the p53–cyclophilin
D interaction using molecular dynamics simulations and associated
analyses. We have identified the specific cyclophilin D binding site
on p53 that is located at proline 151 in the DNA binding domain. As
a peptidyl-prolyl isomerase, cyclophilin D binds p53 and catalyzes
the cis–trans isomerization of the peptide
bond preceding proline 151. We have also characterized the effect
of such an isomerization and found that the p53 domain in the cis state is overall more rigid than the trans state except for the local region around proline 151. Dynamical
changes upon isomerization occur in both local and distal regions,
indicating an allosteric effect elicited by the isomerization. We
present potential allosteric communication pathways between proline
151 and distal sites, including the DNA binding surface. Our work
provides, for the first time, a model for how cyclophilin D binds
p53 and regulates its activity by switching the configuration of a
specific site.