Metal substitution in transferrins: specific binding of cerium(IV) revealed by the crystal structure of cerium-substituted human lactoferrin.
Proteins of the transferrin family play a key role in iron homeostasis through their extremely strong binding of iron, as Fe3+. They are nevertheless able to bind a surprisingly wide variety of other metal ions. To investigate how metal ions of different size, charge and coordination characteristics are accommodated, we have determined the crystal structure of human lactoferrin (Lf) complexed with Ce4+. The structure, refined at 2.2 A resolution (R=20.2%, Rfree=25.7%) shows that the two Ce4+ ions occupy essentially the same positions as do Fe3+, and that the overall protein structure is unchanged; the same closed structure is formed for Ce2Lf as for Fe2Lf. The larger metal ion is accommodated by small shifts in the protein ligands, made possible by the presence of water molecules adjacent to each binding site. The two Ce4+ sites are equally occupied, indicating that the known difference in the pH-dependent release of Ce4+ arises from a specific protonation event, possibly of the His ligand in one of the binding sites. Comparing the effects of binding Ce4+ with those for the binding of other metal ions, we conclude that the ability of transferrins to accommodate metal ions other than Fe3+ depends on an interplay of charge, size, coordination and geometrical preferences of the bound metal ion. However, it is the ability to accept the six-coordinate, approximately octahedral, site provided by the protein that is of greatest importance.
Baker
H M
HM
School of Biological Sciences, University of Auckland, New Zealand.
Baker
C J
CJ
Smith
C A
CA
Baker
E N
EN
D002563:Cerium / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D007781:Lactoferrin / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D014168:Transferrin / Q000737:chemistry*
D014168:Transferrin; D002563:Cerium; D007781:Lactoferrin