Lactoferrin, iron coordination

Fig. 4. The iron coordination in lactoferrin at 3.2-A resolution. (Reproduced from Ref. Ill with the authors permission.)...

Detailed pictures of the iron-binding sites in transferrins have been provided by the crystal structures of lactoferrin (Anderson et ai, 1987, 1989 Baker etai, 1987) and serum transferrin (Bailey etal., 1988). Each structure is organized into two lobes of similar structure (the amino- and carboxy-terminal lobes) that exhibit internal sequence homology. Each lobe, in turn, is organized into two domains separated by a cleft (Fig. 3 and 10). The domains have similar folding patterns of the a//3 type. One iron site is present in each lobe, which occupies equivalent positions in the interdomain cleft. The same sets of residues serve as iron ligands to the two sites two tyrosines, one histidine, and one aspartate. Additional extra density completes the octahedral coordination of the iron and presumably corresponds to an anion and/or bound water. The iron sites are buried about 10 A below the protein surface and are inaccessible to solvent. 

Coordinates for human lactoferrin, in both diferric (78) and apo- (80) forms, for diferric rabbit serum transferrin (68), and for the three fragment structures, the proteolytic N-lobe of rabbit serum transferrin (74), the recombinant N-lobe of human lactoferrin (75) and the duck ovotransferrin quarter-molecule (76), all in their iron-bound forms, can be obtained from the Brookhaven Protein Data Bank (Brookhaven National Laboratory, Upton, New York). 

Iron is then reoxidized to Fe in an aerobic environment and coordinated by lactoferrin released from the secondary granules of neutrophils. The resultant lactoferrin-Fe is taken up by specific receptors on macrophages (102,103). The transport of the iron, implicated as the target of neutrophilic inflammation, concludes as the metal is stored in ferritin (104,105). This deposition in the macrophage is histologically detected as a sideromacrophage and can be a reliable marker of neutrophilic inflammation (102,106,107). 

Rather than being a maladaptive response, the inflammation initiated and coordinated by arachidonic acid products and cytokines after exposure to mineral oxides is absolutely essential for the survival of the host. The iron was initially complexed to the dust with a labile or reactive coordination site available. Consequently, the metal was capable of oxidant generation and injury to host tissues. After reduction by superoxide produced by NADPH oxidoreductase in the neutrophil, reaction with lactoferrin released by the neutrophil (108), and deposition in ferritin of the reticuloendothelial system (109), the iron is rendered catalytically less active. 

---