The structural mechanism for iron uptake and release by transferrins

Transferrins are a group of iron-binding proteins that control the levels of iron in the body fluids of vertebrates by their ability to bind two Fe3+ and two CO3(2-). The transferrin molecule, with a molecular mass of about 80 kDa, is folded into two similarly sized homologous N- and C-lobes that are stabilized by many intrachain disulfides. As observed by X-ray crystallography, each lobe is further divided into two similarly sized domains, domain 1 and domain 2, and an Fe3+-binding site is within the interdomain cleft. Four of the six Fe3+ coordination sites are occupied by protein ligands (2 Tyr residues, 1 Asp, and 1 His) and the other two by a bidentate CO3(2-). Upon uptake and release of Fe3+, transferrins undergo a large-scale conformational change depending on a common structural mechanism: domains 1 and 2 rotate as rigid bodies around a rotation axis that passes through the two antiparallel beta-strands linking the domains. The extent of the rotation is, however, variable for different transferrin species and lobes. As a Fe3+ release mechanisms at low pH from the N-lobes of serum transferrin and ovotransferrin, the structural evidence for 'dilysine trigger mechanism' is shown. A structural mechanism for the Fe3+ release in presence of a non-synergistic anion is proposed on the basis of the sulfate-bound apo crystal structure of the ovotransferrin N-lobe. Domain-opened structures with the coordinated Fe3+ by the two tyrosine residues are demonstrated in fragment and intact forms, and their functional implications as a possible intermediate for iron uptake and release are discussed.