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Literature summary for 7.2.2.9 extracted from

  • Veldhuis, N.A.; Gaeth, A.P.; Pearson, R.B.; Gabriel, K.; Camakaris, J.
    The multi-layered regulation of copper translocating P-type ATPases (2009), Biometals, 22, 177-190.
    View publication on PubMed

Cloned(Commentary)

Cloned (Comment) Organism
rescue and correction of the Cu accumulation defect by expression of wild type MNK in non-polarized BHK cells Homo sapiens

Protein Variants

Protein Variants Comment Organism
additional information apical/subapical MNK distribution of the MNK L1487-1488A mutant Homo sapiens

Localization

Localization Comment Organism GeneOntology No. Textmining
membrane
-
Homo sapiens 16020
-
membrane
-
Saccharomyces cerevisiae 16020
-
additional information mechanisms for copper-ATPase trafficking, detailed overview Homo sapiens
-
-
additional information mechanisms for copper-ATPase trafficking, detailed overview Saccharomyces cerevisiae
-
-

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
ATP + H2O + Cu2+/in Saccharomyces cerevisiae
-
ADP + phosphate + Cu2+/out
-
?
ATP + H2O + Cu2+/in Homo sapiens the copper-translocating Menkes, ATP7A or MNK protein, and Wilson, ATP7B or WND protein, P-type ATPases are pivotal for copper homeostasis, functioning in the biosynthetic incorporation of Cu into copper-dependent enzymes of the secretory pathway, Cu detoxification via Cu efflux, and specialized roles such as MNK in systemic Cu absorption and WND in Cu excretion. MNK and WND Cu-ATPases translocate Cu across biological membranes, MNK participates in vectorial Cu transport across the basolateral membrane and into the bloodstream. Phosphorylation events play a central role in Cu homeostasis, promoting multi-layered regulation and cross-talk between cuproenzymes and Cu-independent mechanisms, overview. MNK is responsible for direct Cu export in response to lactation, where hormonal induction by estrogen, progesterone, insulin and prolactin stimulate the expression and basolateral localization of MNK and the Cu uptake protein Ctr1 to perform a homeostatic function in the mother’s tissue ADP + phosphate + Cu2+/out
-
?
additional information Homo sapiens both Menkes and Wilson Disease are severe inherited human diseases involving dysfunctional Cu homeostasis, caused by mutations in the ATP7A and ATP7B genes, respectively. MNK function is linked to activation of the N-methyl-D-aspartic, NMDA, receptor by glycine-glutamate stimulating synaptic release of intracellular Cu, where upon NMDA activation MNK undergoes rapid, reversible relocalization from the TGN to post-Golgi neuronal processes for Cu release. Role for WND in apical Cu excretion and storage in Cu-loaded vesicles, whereas Cu-stimulated MNK trafficking from internal secretory compartments to the basolateral membrane aids Cu re-absorption ?
-
?

Organism

Organism UniProt Comment Textmining
Homo sapiens
-
-
-
Saccharomyces cerevisiae
-
-
-

Posttranslational Modification

Posttranslational Modification Comment Organism
phosphoprotein both MNK and WND are phosphorylated on serine residues, indicating a key role for one or more serine/threonine kinases for regulation of their trafficking and possibly function Homo sapiens
phosphoprotein Ccc2 N-terminal phosphorylation may be coupled to the ATPase domain catalytic cycle. Protein kinase A phosphorylation site at Ser258 is located between MBD6 and the first transmembrane domain, Cu is predicted to promote Ser258 phosphorylation by increasing solvent accessibility of the region as a consequence of Cu-MBD interactions Saccharomyces cerevisiae

Source Tissue

Source Tissue Comment Organism Textmining
enterocyte
-
Homo sapiens
-
fibroblast
-
Homo sapiens
-
hippocampus
-
Homo sapiens
-
mammary gland
-
Homo sapiens
-
neuron hippocampal, neuronal MNK trafficking may occur independently of its catalytic cycle Homo sapiens
-
placenta
-
Homo sapiens
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
ATP + H2O + Cu2+/in
-
Homo sapiens ADP + phosphate + Cu2+/out
-
?
ATP + H2O + Cu2+/in
-
Saccharomyces cerevisiae ADP + phosphate + Cu2+/out
-
?
ATP + H2O + Cu2+/in the copper-translocating Menkes, ATP7A or MNK protein, and Wilson, ATP7B or WND protein, P-type ATPases are pivotal for copper homeostasis, functioning in the biosynthetic incorporation of Cu into copper-dependent enzymes of the secretory pathway, Cu detoxification via Cu efflux, and specialized roles such as MNK in systemic Cu absorption and WND in Cu excretion. MNK and WND Cu-ATPases translocate Cu across biological membranes, MNK participates in vectorial Cu transport across the basolateral membrane and into the bloodstream. Phosphorylation events play a central role in Cu homeostasis, promoting multi-layered regulation and cross-talk between cuproenzymes and Cu-independent mechanisms, overview. MNK is responsible for direct Cu export in response to lactation, where hormonal induction by estrogen, progesterone, insulin and prolactin stimulate the expression and basolateral localization of MNK and the Cu uptake protein Ctr1 to perform a homeostatic function in the mother’s tissue Homo sapiens ADP + phosphate + Cu2+/out
-
?
ATP + H2O + Cu2+/in Ccc2 N-terminal phosphorylation may be coupled to the ATPase domain catalytic cycle Saccharomyces cerevisiae ADP + phosphate + Cu2+/out
-
?
additional information both Menkes and Wilson Disease are severe inherited human diseases involving dysfunctional Cu homeostasis, caused by mutations in the ATP7A and ATP7B genes, respectively. MNK function is linked to activation of the N-methyl-D-aspartic, NMDA, receptor by glycine-glutamate stimulating synaptic release of intracellular Cu, where upon NMDA activation MNK undergoes rapid, reversible relocalization from the TGN to post-Golgi neuronal processes for Cu release. Role for WND in apical Cu excretion and storage in Cu-loaded vesicles, whereas Cu-stimulated MNK trafficking from internal secretory compartments to the basolateral membrane aids Cu re-absorption Homo sapiens ?
-
?

Synonyms

Synonyms Comment Organism
ATP7A
-
Homo sapiens
ATP7B
-
Homo sapiens
Ccc2
-
Saccharomyces cerevisiae
copper translocating P-type ATPase
-
Homo sapiens
copper-ATPase
-
Saccharomyces cerevisiae
copper-translocating Menkes P-type ATPase
-
Homo sapiens
copper-translocating Wilson P-type ATPase
-
Homo sapiens
Cu-ATPase
-
Saccharomyces cerevisiae
MNK
-
Homo sapiens
MNK Cu-ATPase
-
Homo sapiens
WND
-
Homo sapiens
WND Cu-ATPase
-
Homo sapiens

Cofactor

Cofactor Comment Organism Structure
ATP
-
Homo sapiens
ATP
-
Saccharomyces cerevisiae