Solving the structure of human H ferritin by genetically engineering intermolecular crystal contacts.
Ferritin is important in iron homeostasis. Its twenty-four chains of two types, H and L, assemble as a hollow shell providing an iron-storage cavity. Ferritin molecules in cells containing high levels of iron tend to be rich in L chains, and may have a long-term storage function, whereas H-rich ferritins are more active in iron metabolism. The molecular basis for the greater activity of H-rich ferritins has until now been obscure, largely because the structure of H-chain ferritin has remained unknown owing to the difficulties in obtaining crystals ordered enough for X-ray crystallographic analysis. Here we report the three-dimensional structure of a human ferritin H-chain homopolymer. By genetically engineering a change in the sequence of the intermolecular contact region, we obtained crystals isomorphous with the homologous rat L ferritin and of high enough quality for X-ray diffraction analysis. The X-ray structure of human H ferritin shows a novel metal site embedded within each of its four-helix bundles and we suggest that ferroxidase activity associated with this site accounts for its rapid uptake of iron.
Lawson
D M
DM
Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, University, Sheffield, UK.
Artymiuk
P J
PJ
Yewdall
S J
SJ
Smith
J M
JM
Livingstone
J C
JC
Treffry
A
A
Luzzago
A
A
Levi
S
S
Arosio
P
P
Cesareni
G
G
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D003196:Computer Graphics; D003461:Crystallography; D005293:Ferritins / Q000235:genetics / Q000648:ultrastructure*; D006801:Humans; D007501:Iron / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D008970:Molecular Weight; D051381:Rats; D011994:Recombinant Proteins; D014961:X-Ray Diffraction
D011994:Recombinant Proteins; D005293:Ferritins; D007501:Iron