COPPER TRANSPORTING ATPases

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COPPER TRANSPORTING ATPases

• Sean Akhavan
• Lara Atchabahian
• Shahryar Barzegar
• Karen Ekizian
• Amir Rowshanrad

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COPPER

• Plays a critical role in human metabolism
• It is a cofactor in key metabolic enzymes
  involved in physiological functions
• Average daily intake is about 1-3 mg
• Major of absorption takes place in the small
  intestine

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Overview of Copper Metabolism in the Body

• Copper is exported from the enterocytes
  (intestinal epithelial cells) into the blood
• Copper in the blood travels mainly to the liver
  (kidney, brain)
• Excess copper is exported from the liver into
  bile

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COPPER DISTRIBUTION IN THE BODY
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DESTINATIONS OF COPPER IN THE CELL

• Mitochondria (cytochrome c oxidase)
• Copper, Zinc Superoxide Dismutase 1
• Secretory Pathway

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COPPER ATPase

• Part of a larger family of heavy metal
  transporters
• Responsible for the transport of metals

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Two Classes of Cu-Transport ATPases ATP7A and
ATP7B

• ATP7A
• Copper delivery via intestine to the body and to
  the brain
• Expressed in vascular smooth muscle cells,
  vascular endothelial cells, and aorta
• Role in Central Nervous System
• Menkes Disease
• ATP7B
• ATP7B is involved in the biosynthesis of copper
  containing proteins in hepatocytes
• Export of excess copper into the bile in
  hepatocytes
• Effect on Cis-platin based chemotherapy
• Wilson Disease

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SECRETORY PATHWAY

• Trans-Golgi network (TGN) contains Cu-ATPases
  (ATP7B in hepatocytes)
• ATPase transfer cytosolic copper into the lumen
  of the Golgi
• Once inside the lumen copper is incorporated into
  copper-dependant ferroxidase ceruloplasmin (CP)
• CP is a copper-containing serum protein
• Excess cytosolic copper is excreted into the bile
  

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STRUCTURE OF COPPER ATPase

• Have 6-8 transmembrane segments
• Only one pair of transmembrane segments are on
  the carboxy terminal side of the cytoplasmic
  ATP-binding domain
• Contains a highly hydrophobic region preceding
  the TGEA conserved motif
• Has a large N-terminal cytosolic domain
• contains between 1 and 6 copies of a metal
  binding repeat GMTCXXC
• variable number of repeats leads to diversity of
  molecular weights within the ATPases

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STRUCTURE OF COPPER ATPase

• TGEA is located in the cytoplasmic loop between
  transmembrane segments 4 and 5
• used in energy transduction
• DKTG, SEPHPL, and GDGXND are located in the large
  cytoplasmic loop between transmembrane segments 6
  and 7.
• DKTG contains conserved aspartic acid residue
  that is phosphorylated in the transport cycles of
  the proteins
• GDGXND it is highly alpha-helical
• SEHPL is present only in heavy metal transporting
  P-type ATPases

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COPPER ATPase STRUCTURE
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STRUCTURE OF COPPER ATPase
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METAL BINDING DOMAIN

• Has a high affinity for Zn (II)
• Relative to Zn (II), Cd(II), Au (III) and Hg(II)
  have the highest affinities for the domain
• Mn (II) and Ni(II) have little or no affinity
• At low concentrations, Cu is able to decrease
  Zn(II)-binding
• As the concentration of Cu is raised, the
  affinity for Cu increases rapidly

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WILSON AND MENKES DISEASE

• Localized in the membrane of the Golgi apparatus
• Gene encodes for Copper-transporting ATPases
• Large cytosolic N-terminal domain contains 6
  tandemly repeated metal-binding motifs of 30
  amino acids

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WILSON DISEASE

• Autosomal recessive disorder
• Gene is expressed predominantly in the liver,
  kidney, and placenta
• Causes toxic accumulation of Cu in the liver and
  brain
• Leads to progressive hepatic and neurological
  damage
• Mutations in this disease cause toxic
  accumulation of Cu in those cells where the gene
  is expressed
• It has a 78 amino acid deletion in the ATPase
  between the first and second metal-binding domains

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WILSON DISEASE
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WILSON DISEASE

• When Cu binds to the N-terminal domain of the
  Wilson disease ATPase, there is a conformational
  change in the protein involving both secondary
  and tertiary structures.
• As small increments of Cu are added, a
  progressive increase in the secondary structure
  is seen

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MENKES DISEASE

• X-linked genetic disorder
• Causes copper deficiency
• Leads to progressive neurodegeneration and death
  in children
• Fatal
• Expressed in the intestine and all tissues except
  the liver
• Mutations in this disease cause copper deficiency
  and the lack of Cu incorporation in important
  enzymes.

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CONCLUSION

• Copper is a cofactor
• There are two types of Copper ATPases
• ATP7A
• ATP7B
• Mutations can lead to Menkes and Wilson Disease