caeruloplasmin structure-function pdb file display

Structure and Functional Sites in Human Caeruloplasmin

Some progress has been made on the identification of which regions of the structure have particular functions and which regions act as binding sites for the various substrates in caeruloplasmin catalysis. These are described in more detail by Bielli and Calabrese.

The structures of the sites can be better examined with the aid an interactive Chime view of of the 1KCW structure.

Binding and Active Sites

Proxidant: A

Peroxidase: B

Amine: C

LSD: D

Fe^II: E

Coppers: F, G, H

NO: I,J

Fe^III: K

A: The Proxidant Site

Histidine 426 is described as the proxidant site, responsible for ceruloplasmin's involvement in oxidative damage to proteins. This may be important in LDL (low density lipoprotein) oxidation.

B: The Peroxidase Site

Cysteine 699 is described as the peroxidase active site. This site has also got glutathione peroxidase activity, with hydrogen peroxide and/or organic peroxides.

It enables ceruloplasmin to remove ractive intermediates that, in the case of hydrogen peroxide, a membrane permiable oxidant, could even lead to an altered intracellular redox state of vascular cells. The reaction with organic hydroperoxides would have significance in the metabolism of lipid hydroperoxides in the extracellular space - Bielli and Calabrese

C: The Aromatic Amine Site

Para-phenylenediamine is not a natural substrate, but is used in the assay of caeruloplasmin.

D: The Lysergic Acid Diethylamide Site

This is known to act as a modulator of the oxidase activity of caeruloplasmin to bigenic amines. LSD is of course a psychotomimetic, so does mescalin have a similar course? Caeruloplasmin is found in the brain as a membrane-anchored form.

E,K: The Fe^II Binding Site

The ferrous ion can possibly enter here, the region is close to two negatively charged residues anchoring the labile copper atoms. Ferroxidase activity, that is conversion of Fe^II to Fe^III, is probably the most important aspect of caeruloplamin's uses.

The top of the ceruloplasmin molecule appears particularly designed to permit this reaction, in that it is endowed with all the structural elements .. necessary to facilitate the diffusion and the capture of the ferrous ion, its oxidation and selective retention. - Bielli and Calebrese.

F: The Two Labile Coppers

Caeruloplasmin may act as a copper transport protein, and the amount of copper is certainly variable. The X-ray structure reveals two extra 'labile' coppers, and many medical researchers refer to caeruloplasmin as having seven coppers. The discovery that copper metabolism is normal in patients with aceruloplasminaemia demonstartes that the metalloprotein has an essential role in iron but not copper metabolism.

G: The T3₂T2 cluster

This center is responsible in other similar metalloenzymes for the conversion of dioxygen into water. It is important that this feat is accomplished without the release of any of the (nasty!) possible intermediates in this reaction, namely hydrogen peroxide or superoxide radicals.

H: The T1 coppers

These are the 'electron transfer' coppers, responsible for the transfer of electrons in and out of the cupredoxins, the one close to the copper cluster is generally thought to ferry electrons into this to aid its reduction of dioxygen.

I,J: Nitric Oxide

I, could be an entry point for nitric oxide, J, it's exit in the form of S-nitrosoglutathione. Nitric oxide is a new entry onto the list of substrates for caeruloplasmin.