CCS (gene) explained

Copper chaperone for superoxide dismutase is a metalloprotein that is responsible for the delivery of Cu to superoxide dismutase (SOD1).[1] 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.[2] [3] 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.[3] In humans the protein is encoded by the CCS gene.[4] [5]

Structure and function

CCS is composed of three domains.[1] Domain I is located on the N-terminus and contains the MXCXXC Cu binding sequence.[1] It has been determined to be necessary for function of CCS but its specific role is currently unknown.[1] The structure of domain II greatly resembles that of SOD1 which allows it to perform the function of binding to SOD1.[1] Domain III contains a CXC Cu binding motif and performs the Cu insertion and subsequent disulfide oxidation of SOD1.[1]

When CCS docks to SOD1, cysteine 244 of CCS and 57 of SOD1 form a disulfide linkage.[2] This disulfide bond is then transferred to form a disulfide bridge between cysteine 57 and 146 of SOD1.[2] CCS's catalytic oxidation of SOD1's disulfide bridge can only be performed in the presence of oxygen.[2] Furthermore, the disulfide linkage of SOD1 can be performed without the presence of CCS but requires oxygen and is much slower.[2] Additionally, CCS is proposed to help the proper folding of SOD1 by binding in the apo-state.[2]

As well as SOD1, CCS (gene) has been shown to interact with APBA1.[6]

Localization

CCS is localized in the nucleus, cytosol, and mitochondrial intermembrane space.[3] CCS is imported to the mitochondria by Mia40 and Erv1 disulfide relay system.[3] The cysteine 64 of CCS Domain I generates a disulfide intermediate with Mia40.[3] 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.[2] [3]

Role in copper homeostasis

In mammals cellular Cu levels are regulated by CCS's interaction with the 26S proteasome.[3] During times of Cu excess CCS delivers Cu to XIAP and primes the complex for auto-ubiquitination and subsequent degradation.[3] Expression of SOD1 is not modified by Cu availability but by CCS ability to deliver Cu.[3] 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.[3]

Cells with CCS mutants have been shown to display ALS like symptoms.[2] Moreover, SOD1 mutants that have altered interactions with CCS have been shown to display misfolding and aggregation.[2]

Further reading

Notes and References

  1. Fukai T, Ushio-Fukai M . Superoxide dismutases: role in redox signaling, vascular function, and diseases . Antioxidants & Redox Signaling . 15 . 6 . 1583–1606 . Sep 2011 . 21473702 . 10.1089/ars.2011.3999 . 3151424.
  2. Son M, Elliott JL . Mitochondrial defects in transgenic mice expressing Cu,Zn superoxide dismutase mutations: the role of copper chaperone for SOD1 . Journal of the Neurological Sciences . 336 . 1–2 . 1–7 . Jan 2014 . 24269091 . 10.1016/j.jns.2013.11.004 . 7959466 .
  3. Nevitt T, Ohrvik H, Thiele DJ . Charting the travels of copper in eukaryotes from yeast to mammals . Biochimica et Biophysica Acta (BBA) - Molecular Cell Research . 1823 . 9 . 1580–1593 . Sep 2012 . 22387373 . 10.1016/j.bbamcr.2012.02.011 . 3392525.
  4. Culotta VC, Klomp LW, Strain J, Casareno RL, Krems B, Gitlin JD . The copper chaperone for superoxide dismutase . The Journal of Biological Chemistry . 272 . 38 . 23469–72 . Sep 1997 . 9295278 . 10.1074/jbc.272.38.23469 . free .
  5. Web site: Entrez Gene: CCS copper chaperone for superoxide dismutase.
  6. McLoughlin DM, Standen CL, Lau KF, Ackerley S, Bartnikas TP, Gitlin JD, Miller CC . The neuronal adaptor protein X11alpha interacts with the copper chaperone for SOD1 and regulates SOD1 activity . The Journal of Biological Chemistry . 276 . 12 . 9303–7 . Mar 2001 . 11115513 . 10.1074/jbc.M010023200 . free .

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