ENVIRONMENTAL CONTROL OF IRON AND SYNERGISTIC ANION RELEASE FROM FERRIC BINDING PROTEIN
Canan Atilgan*, Gokce Guven, Ali Rana Atilgan
Human transferrin (hTF) binds and delivers Fe+3 to cells; lowered pH within the endosome (5.6) is implicated in the controlled release of bound ions . Although the kinetics of the process is well studied, detailed molecular mechanisms at work are unknown. Bacterial transferrin, also known as ferric binding protein(FBP), is involved in scavenging iron from hTf . These host/pathogen iron uptake proteins are thought to be distantly related through divergent evolution from an anion binding function; FBP displays similarity to one of the iron binding lobes of hTf in structural fold and highly conserved set of iron-coordinating residues.
Perturbation response scanning (PRS) takes advantage of the differences between ligand-bound/unbound conformations to decipher residues having a direct effect on binding mechanisms . PRS on apo and holo forms of FBP implicates D52, a charged residue located ca. 30Å from the bound ion, as playing a crucial role in ion release. Using pKa calculations  we ﬁnd D52 is the most sensitive to subtle pH variations in the physiological range. The effects of protonating D52, D52A mutation, ionic strength changes and lowering pH in both the apo and holo forms were investigated by extensive molecular dynamics simulations. Our results lend clues as to how the environmental conditions may be utilized for controlling conformation distributions in iron transport proteins such as FBP and hTf.
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Canan Atilgan is a Professor of Engineering and Natural Sciences at Sabanci University. Her current research focuses on theoretical and computational investigation of complex molecular systems, with emphasis on protein structure and dynamics. For more info. see http://people.sabanciuniv.edu/~canan and http://midst.sabanciuniv.edu/.