Structure to function relationships in ceruloplasmin: a 'moonlighting' protein

Abstract

Specialised copper sites have been recruited during evolution to provide long-range electron transfer reactivity and oxygen binding and activation in proteins destined to cope with oxygen reactivity in different organisms. Ceruloplasmin is an ancient multicopper dase evolved to insure a safe handling of oxygen in some metabolic pathways of vertebrates. The presently available knowledge of its structure provides a glimpse of its plasticity, revealing a multitude of binding sites that point to an elaborate mechanism of multifunctional activity. Ceruloplasmin represents an example of a 'moonlighting' protein that overcomes the one gene-one structure-one function concept to follow the changes of the organism in its physiological and pathological conditions.

Ceruloplasmin fragmentation is implicated in 'free' copper deregulation of Alzheimer disease

“…21,22 Consequently, the idea of an impairment also in AD of copper incorporation into ceruloplasmin simply comes from the notion that the ceruloplasmin apo-protein is rapidly degraded in plasma secondary to a defect in copper incorporation. [21][22][23] In other words, the identification of <50 kDa ceruloplasmin fragments in AD general circulation appears as the sign of an impairment of copper transfer into the secretory pathway of hepatocytes that could, at least in part, account for the rise of the 'free' copper portion found in AD. Ceruloplasmin fragmentation, together with the 'free' copper rise in AD, could be the cause or the result of a disturbed hepatocytes function, possibly resulting in liver hypometabolism.…”

Involvement of Glycosylphosphatidylinositol-linked Ceruloplasmin in the Copper/Zinc-Nitric Oxide-dependent Degradation of Glypican-1 Heparan Sulfate in Rat C6 Glioma Cells

“…However, within the intracellular compartments or under the cell-free conditions used here, the copper in Cp may be available for other Cu(II)-mediated reactions. This may involve only the copper bound at His-426 or also other copper atoms in Cp (21)(22)(23).…”

Ceruloplasmin Protects Injured Spinal Cord from Iron-Mediated Oxidative Damage

“…1i-k) (supplemental Fig. 2, available at www.jneurosci.org as supplemental material), we speculate based on the literature on the ferroxidase functions of Cp (Bielli and Calabrese, 2002;Hellman and Gitlin, 2002) that the iron released from these macrophages may not be safely oxidized and may therefore remain in the toxic ferrous state.…”