Albany 2015:Book of Abstracts
June 9-13 2015
©Adenine Press (2012)
Influence of iron on iron dependent repressor (IdeR) activation and DNA binding
Metalloproteins form a major class of enzymes in the living system and are involved in critical biological functions such as catalysis, redox reactions and as "switches" in signal transductions. Iron dependent repressor (IdeR) is a metal-sensing transcription factor that regulates free iron concentration in Mycobacterium tuberculosis. IdeR is also known to promote bacterial virulence, making it an important protein for therapeutics.
In this study, we have performed molecular dynamic simulations of IdeR in the presence and absence of iron to study the influence of iron on IdeR structure and function. Structures were investigated using a combination of molecular dynamics and protein structure networks for a set of 7 different forms of IdeR. A significant variation between the metallated and the non-metallated system is observed in all the cases. Our studies could establish the role of iron in stabilizing the monomeric unit of IdeR which in turn promotes protein dimerization. Dynamics of IdeR also indicated the presence of two major conformations, the 'open' and 'closed' conformations, geometrical properties of which were investigated thoroughly. Shift in energy landscape of the monomers as a result of iron binding was also established.
Perhaps, the most striking results are obtained from the simulations of the IdeR-DNA complex in the absence of metals, where the protein subunits are seen to rapidly dissociate away from the DNA. Such drastic changes in the IdeR-DNA interactions not only provide molecular insights about the mechanism of DNA binding and unbinding, but also underscores the importance of iron for IdeR function. Our analysis also suggests that iron could be an allosteric effector of the protein, as defined by the population shift model of allostery. Different possible scenarios of the allosteric mode of interactions have also been explored and understood in details.
Finally, collating observations from our simulations studies and other experimental measures, we propose a model of IdeR activation and DNA binding. A key feature of the model is that iron acts as an allosteric effector that prepares the structure for DNA binding and also enhances IdeR-DNA interactions.
1I.I.Sc Mathematics Initiative