The Crystal Structures of Caeruloplasmin and Related Metalloproteins

The structure of the protein shows six domains, a feature which was discovered over twenty years ago by an electron microscope investigation. This study also established the molecular weight of 130kD. The six domains are arranged in a triangular array, and each domain has a beta-barrel with strands like those in other cupredoxins such as azurin or plastocyanine. In the diagram the even barrels are coloured blue, the odd ones yellow. {Diagram after Zaitseva et al} The X-ray crystal structure shows that there are also six non-labile copper atoms. Three of these form a trinuclear cluster (like that in ascorbate oxidase) and situated at the interface of domains 1 and 6. The coppers are only coordinated to histidine nitrogens. The trimer is made from a T3 copper pair and a T2 copper, and as in ascorbate oxidase a hydroxide bridges the T3 pair, and a single hydroxide sits on the T2 site. The human caeruloplasmin structure has a very strong kinship with the structure of ascorbate oxidase, with a T1 copper at 1200-1300pm. Nitrite reductans, another copper oxidase, has a similar three domain structure. {Multi-copper is certainly appropriate with nitrite reductans} The three other T1 coppers are in the even domains 2,4 and 6. Two of the T1 coppers have four coordination, with two nitrogen abd two sulphur ligands. The other T1 copper is trigonally coordinated, more like plastocyanin, however there is a leucine residue which replaces the methionines of the other two T1 coppers, but at a van der Waals contact distance.

The six copper atoms are arranged into two large triangles, however the triangles are not in the same plane, a feature best seen via the crystal structure. In addition to the six coppers there are also two additional labile coppers. Some progress has been made in establishing the structure-function relationships for the caeruloplasmins.