University of Vermont

College of Medicine

Department of Biochemistry

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Human serum transferrin and its specific receptor-Partners in iron delivery to cells

Human serum transferrin is a member of a family (includes serum transferrin, ovotransferrin & lactoferrin) that bind iron with different affinities in each of two lobes, although all lobes have identical amino acid ligands to the iron. Iron sequestration and transport by serum transferrin and delivery of this iron to cells by pH dependant, receptor mediated endocytosis, are biologically critical functions. My research program has sought to mechanistically understand iron release from the individual lobes of human serum transferrin and the egg white protein ovotransferrin, especially in a complex with their respective receptors. We have clearly shown that both lobes of transferrin interact with each other and with the receptor to bring about release of this vital metal to actively dividing cells. For example, developing red blood cells (reticulocytes) require iron for heme synthesis which is a prerequisite to making the hemoglobin that is essential to oxygen transport in the body. Key to our work is our ability to make large amounts of recombinant transferrin and of site-directed mutants, as well as the soluble portion of the transferrin receptor in a robust mammalian expression system. The rate constants for iron release in the presence and absence of the soluble transferrin receptor (as a function of pH and anion concentration) are routinely measured. The capture and definitive assignment of all kinetic events associated with iron release by stopped flow spectrofluorimetry, in the presence and absence of the TFR, has unequivocally established the decisive role of the TFR in promoting efficient and balanced iron release from both lobes of hTF during a single endocytic cycle  [Byrne et al, 2010, see below].  Authentic monoferric (iron in only one lobe) and apo-transferrins (no ability to bind iron in either lobe) provide essential controls. Also, integral to our work is determination of structures of transferrin and some of our mutants allowing us to link structure to function. As an example, the crystal structure of monoferric transferrin bound to the soluble portion of the transferrin receptor [Eckenroth et al, 2011, see below] provided tremendous insight into the role of the receptor in facilitating iron release from the C-lobe and slowing iron release from the N-lobe. Overall we have been able to more precisely identify the steps leading to iron release by identification of the specific residues within each lobe of transferrin and of the transferrin receptor that facilitate the efficient delivery of iron at the right time in the right place. Thus we have helped to establish that the interaction of TF with its specific receptor controls iron distribution in the body. Owing to the fact that iron deficiency (anemia) and excess (hemochromatosis) are directly related to specific human diseases, understanding this process at the molecular level is essential to a global understanding of iron metabolism. Because transferrin bound to its receptor enters cells by endocytosis both entities have been targeted for delivery of toxins to cancer cells which feature large numbers of receptors to promote proliferation.

Last modified May 26 2016 03:50 PM