CP

What is CP protein?

CP (ceruloplasmin) gene is a protein coding gene which situated on the long arm of chromosome 3 at locus 3q24. CP is an important protein secreted by the liver, which plays a key role in the distribution and transport of copper ions in the body and plays an important role in maintaining copper ion homeostasis. Ceruloplasmin is also a ferrous oxidase involved in the metabolism of iron ions in the body. It is a polycopper oxidase containing six copper atoms that bind to specific copper-binding sites as a key factor in the catalytic process. The CP protein is consisted of 1065 amino acids and its molecular mass is approximately 122.2 kDa.

What is the function of CP protein?

CP can bind copper atoms to specific copper binding sites as a key factor in the catalytic process. In addition to its role in copper homeostasis, CP is also a ferrous oxidase that is involved in iron metabolism and is able to oxidize the toxic iron bivalent (Fe2+) to the inactive iron trivalent (Fe3+) form. It also has antioxidant activity and may be involved in controlling the oxidation of cell membrane lipids; In addition, it may play a role in inflammation and immune responses, as ceruloplasmin is an acute phase protein whose levels increase in response to inflammation or tissue damage.

CP Related Signaling Pathway

CP acts as a ferroxidase, playing a crucial role in iron metabolism by catalyzing the oxidation of ferrous iron (Fe2+) to ferric iron (Fe3+), which is then bound to transferrin for transport and storage. A study found that the downregulation of hepatic CP can ameliorate non-alcoholic fatty liver disease (NAFLD) through the SCO1-AMPK-LKB1 complex, indicating a role for CP in energy metabolism and lipid homeostasis. CP has ferroxidase activity that is involved in redox reactions and the regulation of oxidative stress, which is important for cellular homeostasis and defense against reactive oxygen species. CP acts as a ferroxidase, playing a crucial role in iron metabolism by catalyzing the oxidation of ferrous iron (Fe2+) to ferric iron (Fe3+), which is then bound to transferrin for transport and storage.

CP Related Diseases

Aceruloplasminemia is an autosomal recessive disorder caused by a mutation in the CP gene, resulting in the production of little or no CP. This leads to iron accumulation in the brain, pancreas, and liver, causing neurodegeneration and diabetes. CP has been found to be associated with the infiltration of immune cells and acts as a prognostic biomarker in patients with glioma, a type of brain cancer. CP is an acute-phase protein, and its levels can increase in response to inflammation, infection, or tissue damage. Low levels of CP can indicate copper deficiency, which can result in anemia, neutrophil dysfunction, and defects in melanin and elastin synthesis. CP levels can be elevated during pregnancy and in women using oral contraceptives, likely due to hormonal influences.

Fig1. CP participates in the transport of Cu and Fe in the liver. (Zhidong Liu, 2022)

Bioapplications of CP

CP is an important biomarker, and its concentration in serum can reflect the status of a variety of diseases. For example, in Wilson disease, a reduction in CP levels is one of the key indicators for diagnosing the disease. CP is also an important target in drug development. By studying the structure and function of CP, drugs targeting its active site can be designed and developed for the treatment of related diseases.

Case Study 1: Anna Schwantes, 2024

Solid tumors are characterized by hypoxic areas, which are prone for macrophage infiltration. Once infiltrated, macrophages polarize to tumor associated macrophages (TAM) to support tumor progression. Therefore, the crosstalk between TAMs and tumor cells is of current interest for the development of novel therapeutic strategies. These may comprise induction of an iron- and lipid peroxidation-dependent form of cell death, known as ferroptosis. To study the macrophage - tumor cell crosstalk the researchers polarized primary human macrophages towards a TAM-like phenotype, co-cultured them with HT1080 fibrosarcoma cells, and analyzed the tumor cell response to ferroptosis induction. In TAMs the expression of ceruloplasmin mRNA increased, which was driven by hypoxia inducible factor 2 and signal transducer and activator of transcription 1. Subsequently, ceruloplasmin mRNA was transferred from TAMs to HT1080 cells via extracellular vesicles. In tumor cells, mRNA was translated into protein to protect HT1080 cells from RSL3-induced ferroptosis. Mechanistically this was based on reduced iron abundance and lipid peroxidation. Interestingly, in naïve macrophages also hypoxia induced ceruloplasmin under hypoxia and a co-culture of HT1080 cells with hypoxic macrophages recapitulated the protective effect observed in TAM co-cultures.

Fig1. Supernatants were analyzed for ceruloplasmin (CP) by Western analyses.

Fig2. Ceruloplasmin (CP) mRNA was measured and normalized to TATA box binding protein (TBP).

Case Study 2: Eun-Joo Shin, 2015

To determine the role of ceruloplasmin (Cp) in epileptic seizures, the researchers used a kainate (KA) seizure animal model and examined hippocampal samples from epileptic patients. Treatment with KA resulted in a time-dependent decrease in Cp protein expression in the hippocampus of rats. Cp-positive cells were colocalized with neurons or reactive astrocytes in KA-treated rats and epileptic patient samples. KA-induced seizures, initial oxidative stress (i.e., hydroxyl radical formation, lipid peroxidation, protein oxidation, and synaptosomal reactive oxygen species), altered iron status (increasing Fe(2+) accumulation and L-ferritin-positive reactive microglial cells and decreasing H-ferritin-positive neurons), and impaired glutathione homeostasis and neurodegeneration were more pronounced in Cp antisense oligonucleotide (ASO)- than in Cp sense oligonucleotide-treated rats. Consistently, Cp ASO facilitated KA-induced lactate dehydrogenase (LDH) release, Fe(2+) accumulation, and glutathione loss in neuron-rich and mixed cultures. However, Cp ASO did not alter KA-induced LDH release or Fe(2+) accumulation in the astroglial culture, but did facilitate impairment in glutathione homeostasis in the same culture. Importantly, treatment with human Cp protein resulted in a significant attenuation against these neurotoxicities induced by Cp ASO.

Fig3. KA-induced changes in Cp and ferroxidase activity.

Fig4. Hippocampal protein level of Cp after peripheral hCp administration.

CP has several biochemical functions, for example, chaperone binding,copper ion binding,ferroxidase activity. Some of the functions are cooperated with other proteins, some of the functions could acted by CP itself. We selected most functions CP had, and list some proteins which have the same functions with CP. You can find most of the proteins on our site.

CP has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with CP here. Most of them are supplied by our site. Hope this information will be useful for your research of CP.

iron2plus;SLC40A1;q8cl89_yerpe;BTRC;d-mannose;IGHG1;APOA1