title: How the binding of human transferrin primes the transferrin receptor potentiating iron release at endosomal pH.
abstract: Delivery of iron to cells requires binding of two iron-containing human transferrin (hTF) molecules to the specific homodimeric transferrin receptor (TFR) on the cell surface. Through receptor-mediated endocytosis involving lower pH, salt, and an unidentified chelator, iron is rapidly released from hTF within the endosome. The crystal structure of a monoferric N-lobe hTF/TFR complex (3.22-Å resolution) features two binding motifs in the N lobe and one in the C lobe of hTF. Binding of Fe(N)hTF induces global and site-specific conformational changes within the TFR ectodomain. Specifically, movements at the TFR dimer interface appear to prime the TFR to undergo pH-induced movements that alter the hTF/TFR interaction. Iron release from each lobe then occurs by distinctly different mechanisms: Binding of His349 to the TFR (strengthened by protonation at low pH) controls iron release from the C lobe, whereas displacement of one N-lobe binding motif, in concert with the action of the dilysine trigger, elicits iron release from the N lobe. One binding motif in each lobe remains attached to the same α-helix in the TFR throughout the endocytic cycle. Collectively, the structure elucidates how the TFR accelerates iron release from the C lobe, slows it from the N lobe, and stabilizes binding of apohTF for return to the cell surface. Importantly, this structure provides new targets for mutagenesis studies to further understand and define this system.
authors.affiliation: Department of Biochemistry, University of Vermont, 89 Beaumont Avenue, Burlington, VT 05405, USA.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Eckenroth
authors.forename: Ashley N
authors.initials: AN
authors.lastname: Steere
authors.forename: N Dennis
authors.initials: ND
authors.lastname: Chasteen
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Everse
authors.forename: Anne B
authors.initials: AB
authors.lastname: Mason
mesh_terms: D020816:Amino Acid Motifs; D001665:Binding Sites; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007501:Iron / Q000378:metabolism*; D007700:Kinetics; D008958:Models, Molecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011990:Receptors, Transferrin / Q000737:chemistry / Q000378:metabolism*; D014168:Transferrin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D011990:Receptors, Transferrin; D014168:Transferrin; D007501:Iron