Structure of the Human Transferrin Receptor-Transferrin Complex

much is understood of the transferrin endocytotic cy- gistic anion, usually carbonate. The carbonate ion, two cle, little has been uncovered of the molecular details Tyr, a His, and an Asp satisfy the coordination needs of underlying the formation of the receptor-transferrin Fe 3 to form a strong iron binding site in the closed complex. Using cryo-electron microscopy, we have conformation of Tf. Iron release is triggered by a drop produced a density map of the TfR-Tf complex at sub- in pH, which results first in protonation and dissociation nanometer resolution. An atomic model, obtained by of the synergistic anion, followed by protonation of His fitting crystal structures of diferric Tf and the receptor and/or Tyr ligands, and ultimately in release of the iron. ectodomain into the map, shows that the Tf N-lobe For passage across the endosomal membrane via the is sandwiched between the membrane and the TfR iron transporter DMT1, iron must be reduced to the fer- ectodomain and that the C-lobe abuts the receptor rous state; whether such reduction precedes or follows helical domain. When Tf binds receptor, its N-lobe release from transferrin is not clear.