The iron maiden. Cytosolic aconitase/irp1 conformational transition in the regulation of ferritin translation and iron hemostasis

Abstract

Maintaining iron homeostasis is fundamental for almost all living beings, and its deregula-tion correlates with severe and debilitating pathologies. The process is made more complicated by the omnipresence of iron and by its role as a fundamental component of a number of crucial metallo proteins. The response to modifications in the amount of the free-iron pool is performed via the inhibition of ferritin translation by sequestering consensus messenger RNA (mRNA) sequences. In turn, this is regulated by the iron-sensitive conformational equilibrium between cytosolic aconitase and IRP1, mediated by the presence of an iron–sulfur cluster. In this contribution, we analyze by full-atom molecular dynamics simulation, the factors leading to both the interaction with mRNA and the conformational transition. Furthermore, the role of the iron–sulfur cluster in driving the confor-mational transition is assessed by obtaining the related free energy profile via enhanced sampling molecular dynamics simulations.