Transcuprein is a macroglobulin regulated by copper and iron availability

Abstract

Transcuprein is a high-affinity copper carrier in the plasma that is involved in the initial distribution of copper entering the blood from the digestive tract. To identify and obtain cDNA for this protein, it was purified from rat plasma by size exclusion and copper-chelate affinity chromatography, and amino acid sequences were obtained. These revealed a 190-kDa glycosylated protein identified as the macroglobulin alpha(1)-inhibitor III, the main macroglobulin of rodent blood plasma. Albumin (65 kDa) copurified in variable amounts and was concluded to be a contaminant (although it can transiently bind the macroglobulin). The main macroglobulin in human blood plasma (alpha(2)-macroglobulin), which is homologous to alpha(1)-inhibitor III, also bound copper tightly. Expression of alpha(1)I3 (transcuprein) mRNA by the liver was examined in rats with and without copper deficiency, using quantitative polymerase chain reaction methodology and Northern blot analysis. Protein expression was examined by Western blotting. Deficient rats with 40% less ceruloplasmin oxidase activity and liver copper concentrations expressed about twice as much alpha(1)I3 mRNA, but circulating levels of transcuprein did not differ. Iron deficiency, which increased liver copper concentrations by threefold, reduced transcuprein mRNA expression and circulating levels of transcuprein relative to what occurred in rats with normal or excess iron. We conclude that transcupreins are specific macroglobulins that not only carry zinc but also carry transport copper in the blood, and that their expression can be modulated by copper and iron availability.

Copper transporter 1, metallothionein and glutathione reductase genes are differentially expressed in tissues of sea bream (Sparus aurata) after exposure to dietary or waterborne copper

“…Furthermore serum albumin binds Cu in a state which is not available for cellular uptake, although cells will take up Cu 2+ complexed with L-histidine which in blood may couple albumin-bound Cu with cellular uptake systems (Deschamps et al, 2005). The third candidate is transcuprein (also known as α2-macroglubulin and α1-inhibitorIII) and the bulk of copper derived from intestine and thence absorbed by liver is bound to this protein and to serum albumin with which it readily exchanges Cu 2+ (Liu et al, 2007), although conclusive evidence for a central role in Cu transport is still lacking.…”

Uptake of copper from plasma proteins in cells where expression of CTR1 has been modulated

“…In the blood plasma, prevailing evidence indicates that copper destined for uptake by most cells is carried by plasma proteins and not by low molecular weight complexes like with amino acids, at least in the normal state (Linder 1991(Linder , 2010. The three known protein carriers are albumin and transcuprein (a macroglobulin; Liu et al 2007), the main components of the exchangeable plasma copper pool, which bind Cu(II) directly and with high affinity; plus ceruloplasmin, the protein responsible for up to 70% of the copper in human and rat plasma, and somewhat less in the case of the mouse (Cabrera et al 2008;Gray et al 2009). Radioactive copper tracer studies in animals and stable isotope studies in mice indicate that albumin and transcuprein are the first and probably only components to which copper ions initially bind upon entering the blood (Cabrera et al 2008;Linder 1991Linder , 2002Linder , 2010Weiss and Linder 1985;Wirth and Linder 1985).…”

Dietary Copper and the Brain

“…Albumin binds copper with high-affinity via three amino acid residues at its N-terminus (Linder 2002). (iii) Transcuprein -Transcuprein is a macroglobulin and is another high-affinity copper carrier found in the serum of mammals, including humans, rats, and dogs (Liu et al 2007;Hyun and Filippich 2004;Linder 2002;Montaser et al 1992). Both albumin and transcuprein carries 12% each of the total plasma copper and also rapidly exchanges copper with each other (Linder 2002).…”