Protein-coding gene in the species Homo sapiens From Wikipedia, the free encyclopedia
Copper chaperone for superoxide dismutase is a metalloprotein that is responsible for the delivery of Cu to superoxide dismutase (SOD1).[5] CCS is a 54kDa protein that is present in mammals and most eukaryotes including yeast. The structure of CCS is composed of three distinct domains that are necessary for its function.[6][7] Although CCS is important for many organisms, there are CCS independent pathways for SOD1, and many species lack CCS all together, such as C. elegans.[7] In humans the protein is encoded by the CCS gene.[8][9]
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| Aliases | CCS, copper chaperone for superoxide dismutase | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 603864; MGI: 1333783; HomoloGene: 3762; GeneCards: CCS; OMA:CCS - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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CCS is composed of three domains.[5] Domain I is located on the N-terminus and contains the MXCXXC Cu binding sequence.[5] It has been determined to be necessary for function of CCS but its specific role is currently unknown.[5] The structure of domain II greatly resembles that of SOD1 which allows it to perform the function of binding to SOD1.[5] Domain III contains a CXC Cu binding motif and performs the Cu insertion and subsequent disulfide oxidation of SOD1.[5]
When CCS docks to SOD1, cysteine 244 of CCS and 57 of SOD1 form a disulfide linkage.[6] This disulfide bond is then transferred to form a disulfide bridge between cysteine 57 and 146 of SOD1.[6] CCS's catalytic oxidation of SOD1's disulfide bridge can only be performed in the presence of oxygen.[6] Furthermore, the disulfide linkage of SOD1 can be performed without the presence of CCS but requires oxygen and is much slower.[6] Additionally, CCS is proposed to help the proper folding of SOD1 by binding in the apo-state.[6]
As well as SOD1, CCS (gene) has been shown to interact with APBA1.[10]
CCS is localized in the nucleus, cytosol, and mitochondrial intermembrane space.[7] CCS is imported to the mitochondria by Mia40 and Erv1 disulfide relay system.[7] The cysteine 64 of CCS Domain I generates a disulfide intermediate with Mia40.[7] This disulfide bond is transferred to link cysteine 64 and 27 of CCS, stabilizing the protein in the mitochondrial intermembrane space where it delivers Cu to the Cu-less apo-SOD1.[6][7]
In mammals cellular Cu levels are regulated by CCS's interaction with the 26S proteasome.[7] During times of Cu excess CCS delivers Cu to XIAP and primes the complex for auto-ubiquitination and subsequent degradation.[7] Expression of SOD1 is not modified by Cu availability but by CCS ability to deliver Cu.[7] Knockouts of CCS (Δccs) show 70-90% decrease in SOD1 activity as well as increased expression of Cu binding proteins, namely, MT-I, MT-II, ATOX1, COX17, ATP7A to, presumably, reduce the amount of free Cu.[7]
Cells with CCS mutants have been shown to display ALS like symptoms.[6] Moreover, SOD1 mutants that have altered interactions with CCS have been shown to display misfolding and aggregation.[6]
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