CCS (gene)

Last updated
CCS
Protein CCS PDB 1do5.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CCS , copper chaperone for superoxide dismutase
External IDs OMIM: 603864 MGI: 1333783 HomoloGene: 3762 GeneCards: CCS
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_005125

NM_016892

RefSeq (protein)

NP_005116

NP_058588

Location (UCSC) Chr 11: 66.59 – 66.61 Mb Chr 19: 4.88 – 4.89 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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]

Contents

Structure and function

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]

Localization

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]

Role in copper homeostasis

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]

Related Research Articles

<span class="mw-page-title-main">Superoxide dismutase</span> Class of enzymes

Superoxide dismutase (SOD, EC 1.15.1.1) is an enzyme that alternately catalyzes the dismutation (or partitioning) of the superoxide (O
2
) radical into ordinary molecular oxygen (O2) and hydrogen peroxide (H
2
O
2
). Superoxide is produced as a by-product of oxygen metabolism and, if not regulated, causes many types of cell damage. Hydrogen peroxide is also damaging and is degraded by other enzymes such as catalase. Thus, SOD is an important antioxidant defense in nearly all living cells exposed to oxygen. One exception is Lactobacillus plantarum and related lactobacilli, which use a different mechanism to prevent damage from reactive O
2
.

<span class="mw-page-title-main">Metalloprotein</span> Protein that contains a metal ion cofactor

Metalloprotein is a generic term for a protein that contains a metal ion cofactor. A large proportion of all proteins are part of this category. For instance, at least 1000 human proteins contain zinc-binding protein domains although there may be up to 3000 human zinc metalloproteins.

<span class="mw-page-title-main">Calnexin</span> Mammalian protein found in Homo sapiens

Calnexin (CNX) is a 67kDa integral protein of the endoplasmic reticulum (ER). It consists of a large N-terminal calcium-binding lumenal domain, a single transmembrane helix and a short, acidic cytoplasmic tail. In humans, calnexin is encoded by the gene CANX.

<span class="mw-page-title-main">ATP7A</span> Protein-coding gene in humans

ATP7A, also known as Menkes' protein (MNK), is a copper-transporting P-type ATPase which uses the energy arising from ATP hydrolysis to transport Cu(I) across cell membranes. The ATP7A protein is a transmembrane protein and is expressed in the intestine and all tissues except liver. In the intestine, ATP7A regulates Cu(I) absorption in the human body by transporting Cu(I) from the small intestine into the blood. In other tissues, ATP7A shuttles between the Golgi apparatus and the cell membrane to maintain proper Cu(I) concentrations in the cell and provides certain enzymes with Cu(I). The X-linked, inherited, lethal genetic disorder of the ATP7A gene causes Menkes disease, a copper deficiency resulting in early childhood death.

QPNC-PAGE, or QuantitativePreparativeNativeContinuousPolyacrylamideGel Electrophoresis, is a bioanalytical, one-dimensional, high-resolution and high-precision technique applied in biochemistry and bioinorganic chemistry to separate proteins quantitatively by isoelectric point and by continuous elution from a gel column.

<span class="mw-page-title-main">PDIA3</span> Protein-coding gene in the species Homo sapiens

Protein disulfide-isomerase A3 (PDIA3), also known as glucose-regulated protein, 58-kD (GRP58), is an isomerase enzyme encoded by the autosomal gene PDIA3 in humans. This protein localizes to the endoplasmic reticulum (ER) and interacts with lectin chaperones calreticulin and calnexin (CNX) to modulate folding of newly synthesized glycoproteins. It is thought that complexes of lectins and this protein mediate protein folding by promoting formation of disulfide bonds in their glycoprotein substrates.

<span class="mw-page-title-main">SOD1</span> Protein-coding gene in the species Homo sapiens

Superoxide dismutase [Cu-Zn] also known as superoxide dismutase 1 or hSod1 is an enzyme that in humans is encoded by the SOD1 gene, located on chromosome 21. SOD1 is one of three human superoxide dismutases. It is implicated in apoptosis, familial amyotrophic lateral sclerosis and Parkinson's disease.

<span class="mw-page-title-main">Heat shock protein 90kDa alpha (cytosolic), member A1</span> Protein-coding gene in the species Homo sapiens

Heat shock protein HSP 90-alpha is a protein that in humans is encoded by the HSP90AA1 gene.

<span class="mw-page-title-main">HSF1</span> Protein-coding gene in the species Homo sapiens

Heat shock factor 1 is a protein that in humans is encoded by the HSF1 gene. HSF1 is highly conserved in eukaryotes and is the primary mediator of transcriptional responses to proteotoxic stress with important roles in non-stress regulation such as development and metabolism.

<span class="mw-page-title-main">SOD3</span> Protein-coding gene in the species Homo sapiens

Extracellular superoxide dismutase [Cu-Zn] is an enzyme that in humans is encoded by the SOD3 gene.

<span class="mw-page-title-main">ADAMTS4</span> Protein-coding gene in the species Homo sapiens

A disintegrin and metalloproteinase with thrombospondin motifs 4 is an enzyme that in humans is encoded by the ADAMTS4 gene.

<span class="mw-page-title-main">P4HB</span> Protein-coding gene in the species Homo sapiens

Protein disulfide-isomerase, also known as the beta-subunit of prolyl 4-hydroxylase (P4HB), is an enzyme that in humans encoded by the P4HB gene. The human P4HB gene is localized in chromosome 17q25. Unlike other prolyl 4-hydroxylase family proteins, this protein is multifunctional and acts as an oxidoreductase for disulfide formation, breakage, and isomerization. The activity of P4HB is tightly regulated. Both dimer dissociation and substrate binding are likely to enhance its enzymatic activity during the catalysis process.

<span class="mw-page-title-main">APBB1</span> Protein-coding gene in the species Homo sapiens

Amyloid beta A4 precursor protein-binding family B member 1 is a protein that in humans is encoded by the APBB1 gene.

<span class="mw-page-title-main">APBA1</span> Protein-coding gene in the species Homo sapiens

Amyloid beta A4 precursor protein-binding family A member 1 is a protein that in humans is encoded by the APBA1 gene.

<span class="mw-page-title-main">ATOX1</span> Protein-coding gene in the species Homo sapiens

ATOX1 is a copper metallochaperone protein that is encoded by the ATOX1 gene in humans. In mammals, ATOX1 plays a key role in copper homeostasis as it delivers copper from the cytosol to transporters ATP7A and ATP7B. Homologous proteins are found in a wide variety of eukaryotes, including Saccharomyces cerevisiae as ATX1, and all contain a conserved metal binding domain.

<span class="mw-page-title-main">MTF1</span> Protein-coding gene in the species Homo sapiens

Metal regulatory transcription factor 1 is a protein that in humans is encoded by the MTF1 gene.

<span class="mw-page-title-main">GLRX2</span> Protein-coding gene in the species Homo sapiens

Glutaredoxin 2 (GLRX2) is an enzyme that in humans encoded by the GLRX2 gene. GLRX2, also known as GRX2, is a glutaredoxin family protein and a thiol-disulfide oxidoreductase that maintains cellular thiol homeostasis. This gene consists of four exons and three introns, spanned 10 kilobase pairs, and localized to chromosome 1q31.2–31.3.

<span class="mw-page-title-main">Auxilin</span> Protein-coding gene in the species Homo sapiens

Putative tyrosine-protein phosphatase auxilin is an enzyme that in humans is encoded by the DNAJC6 gene.

In molecular biology mir-398 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms.

Valeria Cizewski Culotta is an American molecular biologist.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000173992 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000034108 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 3 4 5 6 Fukai T, Ushio-Fukai M (Sep 2011). "Superoxide dismutases: role in redox signaling, vascular function, and diseases". Antioxidants & Redox Signaling. 15 (6): 1583–1606. doi:10.1089/ars.2011.3999. PMC   3151424 . PMID   21473702.
  6. 1 2 3 4 5 6 7 8 9 Son M, Elliott JL (Jan 2014). "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. doi:10.1016/j.jns.2013.11.004. PMID   24269091. S2CID   7959466.
  7. 1 2 3 4 5 6 7 8 9 10 Nevitt T, Ohrvik H, Thiele DJ (Sep 2012). "Charting the travels of copper in eukaryotes from yeast to mammals". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1823 (9): 1580–1593. doi:10.1016/j.bbamcr.2012.02.011. PMC   3392525 . PMID   22387373.
  8. Culotta VC, Klomp LW, Strain J, Casareno RL, Krems B, Gitlin JD (Sep 1997). "The copper chaperone for superoxide dismutase". The Journal of Biological Chemistry. 272 (38): 23469–72. doi: 10.1074/jbc.272.38.23469 . PMID   9295278.
  9. "Entrez Gene: CCS copper chaperone for superoxide dismutase".
  10. McLoughlin DM, Standen CL, Lau KF, Ackerley S, Bartnikas TP, Gitlin JD, Miller CC (Mar 2001). "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. doi: 10.1074/jbc.M010023200 . PMID   11115513.

Further reading