This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Iron is essential to nearly all forms of life and due to its oxidative potential its levels are strictly regulated. In humans, and many other species, iron homeostasis is mediated by serum transferrin (TF). TF (80 kDa) folds to form two homologous lobes, each composed of two subdomains between which a single Fe3+ atom binds. The acquisition of iron by cells involves the preferential binding of diferric TF to transferrin receptors (TFR) expressed on the plasma membrane. The complex is internalized by endocytosis, acidified by an ATPase pump which leads to iron release ands its transport out of the endosome, and the complex is recycled back to the plasma membrane, where the apo-TF is released to pick up more iron. In vitro experiments in the Mason laboratory has shown that one of the roles of the TFR is to increase the rate of dissociation of iron from the C-lobe while decreasing the rate from the N-lobe (Byrne et al. 2010). Our understanding of the complex took a huge step forward with the publication of the 7.5 ? cryo EM structure of TFR with isolated human N-lobe and rabbit C-lobe (Cheng et al. 2004). This structure supported biochemical data that there are recognition patches in each lobe of TF for the TFR. What was not clear is what residues are interacting, why in other systems both lobes must be associated to achieve binding, and how the structure(s) must change to allow the connection between separated TF lobes. To help answer these and other many other questions we have crystallized a human TF/TFR complex that diffracts to 3.5 ? (home source).ReferencesByrne SL, Chasteen ND, Steere AN, Mason AB. (2010) The unique kinetics of iron release from transferrin: the role of receptor, lobe-lobe interactions, and salt at endosomal pH. J Mol Biol. 396(1):130-40.Cheng Y, Zak O, Aisen P, Harrison SC, Walz T. (2004) Structure of the human transferrin receptor-transferrin complex. Cell. 116(4):565-76.

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