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Role of the P-Type ATPases, ATP7A and ATP7B in brain copper homeostasis.

Telianidis J, Hung YH, Materia S, Fontaine SL - Front Aging Neurosci (2013)

Bottom Line: Our understanding of the biochemistry and cell biology of these complex proteins has grown significantly since their discovery in 1993.Their importance in maintaining brain copper homeostasis is underscored by the severe neuropathological deficits in these disorders.Herein we will review and update our current knowledge of these copper transporters in the brain and the central nervous system, their distribution and regulation, their role in normal brain copper homeostasis, and how their absence or dysfunction contributes to disturbances in copper homeostasis and neurodegeneration.

View Article: PubMed Central - PubMed

Affiliation: Strategic Research Centre for Molecular and Medical Research, School of Life and Environmental Sciences, Deakin University Burwood, VIC, Australia ; Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin University Burwood, VIC, Australia.

ABSTRACT
Over the past two decades there have been significant advances in our understanding of copper homeostasis and the pathological consequences of copper dysregulation. Cumulative evidence is revealing a complex regulatory network of proteins and pathways that maintain copper homeostasis. The recognition of copper dysregulation as a key pathological feature in prominent neurodegenerative disorders such as Alzheimer's, Parkinson's, and prion diseases has led to increased research focus on the mechanisms controlling copper homeostasis in the brain. The copper-transporting P-type ATPases (copper-ATPases), ATP7A and ATP7B, are critical components of the copper regulatory network. Our understanding of the biochemistry and cell biology of these complex proteins has grown significantly since their discovery in 1993. They are large polytopic transmembrane proteins with six copper-binding motifs within the cytoplasmic N-terminal domain, eight transmembrane domains, and highly conserved catalytic domains. These proteins catalyze ATP-dependent copper transport across cell membranes for the metallation of many essential cuproenzymes, as well as for the removal of excess cellular copper to prevent copper toxicity. A key functional aspect of these copper transporters is their copper-responsive trafficking between the trans-Golgi network and the cell periphery. ATP7A- and ATP7B-deficiency, due to genetic mutation, underlie the inherited copper transport disorders, Menkes and Wilson diseases, respectively. Their importance in maintaining brain copper homeostasis is underscored by the severe neuropathological deficits in these disorders. Herein we will review and update our current knowledge of these copper transporters in the brain and the central nervous system, their distribution and regulation, their role in normal brain copper homeostasis, and how their absence or dysfunction contributes to disturbances in copper homeostasis and neurodegeneration.

No MeSH data available.


Related in: MedlinePlus

Schematic diagram of the copper-ATPases, ATP7A and ATP7B. Shown are the highly conserved domains: the N-terminal copper-binding domain, the phosphatase (A-domain), phosphorylation (P-domain), and ATP-binding (N-domain) domains; and the motifs and sequences required for their localization and trafficking. The cylindrical regions labeled 1 -8 represent the transmembrane domains.
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Figure 1: Schematic diagram of the copper-ATPases, ATP7A and ATP7B. Shown are the highly conserved domains: the N-terminal copper-binding domain, the phosphatase (A-domain), phosphorylation (P-domain), and ATP-binding (N-domain) domains; and the motifs and sequences required for their localization and trafficking. The cylindrical regions labeled 1 -8 represent the transmembrane domains.

Mentions: Significant insight into the mechanisms controlling brain copper homeostasis began two decades ago with the identification of the genes encoding the essential copper-transporting ATPases, ATP7A (Chelly et al., 1993; Mercer et al., 1993; Vulpe et al., 1993) and ATP7B (Bull et al., 1993; Petrukhin et al., 1993; Yamaguchi et al., 1993). Mutations in ATP7A and ATP7B underlie MD and WD, respectively. ATP7A is located on chromosome Xq13.2-13.3 and comprises 23 exons that span approximately 150 kb1. ATP7B is located on chromosome 13q14.3 and comprises 21 exons that span approximately 80 kb2. Transcripts of approximately 7.5–8.5 kb are produced from both genes and contain coding regions of 4.5 kb, which are translated to produce proteins of 180 and 165 kDa, respectively. ATP7A and ATP7B are members of the P1B-subfamily of the P-type ATPases. They undergo ATP-dependent cycles of phosphorylation and dephosphorylation to catalyze the translocation of copper across cellular membranes. Their structure and biochemistry was thoroughly reviewed by Lutsenko et al. (2007). They are highly related in structure and function with approximately 60% amino acid identity. They have eight transmembrane domains that form a path through cell membranes for copper translocation; and a large N-terminus with six metal-binding domains (MBDs), each comprising approximately 70 amino acids and the highly conserved metal-binding motif GMxCxxC (where x is any amino acid). Other highly conserved domains include the intramembrane CPC motif that is required for copper translocation through the membrane, the N-domain containing the ATP-binding site, the P-domain containing the conserved aspartic acid residue and the A-domain comprising the phosphatase domain. Copper-binding together with other N- and C-terminal signals regulate their activity, intracellular location, and copper-induced intracellular trafficking (see below and reviewed in La Fontaine and Mercer, 2007; Lutsenko et al., 2007; Figure 1).


Role of the P-Type ATPases, ATP7A and ATP7B in brain copper homeostasis.

Telianidis J, Hung YH, Materia S, Fontaine SL - Front Aging Neurosci (2013)

Schematic diagram of the copper-ATPases, ATP7A and ATP7B. Shown are the highly conserved domains: the N-terminal copper-binding domain, the phosphatase (A-domain), phosphorylation (P-domain), and ATP-binding (N-domain) domains; and the motifs and sequences required for their localization and trafficking. The cylindrical regions labeled 1 -8 represent the transmembrane domains.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750203&req=5

Figure 1: Schematic diagram of the copper-ATPases, ATP7A and ATP7B. Shown are the highly conserved domains: the N-terminal copper-binding domain, the phosphatase (A-domain), phosphorylation (P-domain), and ATP-binding (N-domain) domains; and the motifs and sequences required for their localization and trafficking. The cylindrical regions labeled 1 -8 represent the transmembrane domains.
Mentions: Significant insight into the mechanisms controlling brain copper homeostasis began two decades ago with the identification of the genes encoding the essential copper-transporting ATPases, ATP7A (Chelly et al., 1993; Mercer et al., 1993; Vulpe et al., 1993) and ATP7B (Bull et al., 1993; Petrukhin et al., 1993; Yamaguchi et al., 1993). Mutations in ATP7A and ATP7B underlie MD and WD, respectively. ATP7A is located on chromosome Xq13.2-13.3 and comprises 23 exons that span approximately 150 kb1. ATP7B is located on chromosome 13q14.3 and comprises 21 exons that span approximately 80 kb2. Transcripts of approximately 7.5–8.5 kb are produced from both genes and contain coding regions of 4.5 kb, which are translated to produce proteins of 180 and 165 kDa, respectively. ATP7A and ATP7B are members of the P1B-subfamily of the P-type ATPases. They undergo ATP-dependent cycles of phosphorylation and dephosphorylation to catalyze the translocation of copper across cellular membranes. Their structure and biochemistry was thoroughly reviewed by Lutsenko et al. (2007). They are highly related in structure and function with approximately 60% amino acid identity. They have eight transmembrane domains that form a path through cell membranes for copper translocation; and a large N-terminus with six metal-binding domains (MBDs), each comprising approximately 70 amino acids and the highly conserved metal-binding motif GMxCxxC (where x is any amino acid). Other highly conserved domains include the intramembrane CPC motif that is required for copper translocation through the membrane, the N-domain containing the ATP-binding site, the P-domain containing the conserved aspartic acid residue and the A-domain comprising the phosphatase domain. Copper-binding together with other N- and C-terminal signals regulate their activity, intracellular location, and copper-induced intracellular trafficking (see below and reviewed in La Fontaine and Mercer, 2007; Lutsenko et al., 2007; Figure 1).

Bottom Line: Our understanding of the biochemistry and cell biology of these complex proteins has grown significantly since their discovery in 1993.Their importance in maintaining brain copper homeostasis is underscored by the severe neuropathological deficits in these disorders.Herein we will review and update our current knowledge of these copper transporters in the brain and the central nervous system, their distribution and regulation, their role in normal brain copper homeostasis, and how their absence or dysfunction contributes to disturbances in copper homeostasis and neurodegeneration.

View Article: PubMed Central - PubMed

Affiliation: Strategic Research Centre for Molecular and Medical Research, School of Life and Environmental Sciences, Deakin University Burwood, VIC, Australia ; Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin University Burwood, VIC, Australia.

ABSTRACT
Over the past two decades there have been significant advances in our understanding of copper homeostasis and the pathological consequences of copper dysregulation. Cumulative evidence is revealing a complex regulatory network of proteins and pathways that maintain copper homeostasis. The recognition of copper dysregulation as a key pathological feature in prominent neurodegenerative disorders such as Alzheimer's, Parkinson's, and prion diseases has led to increased research focus on the mechanisms controlling copper homeostasis in the brain. The copper-transporting P-type ATPases (copper-ATPases), ATP7A and ATP7B, are critical components of the copper regulatory network. Our understanding of the biochemistry and cell biology of these complex proteins has grown significantly since their discovery in 1993. They are large polytopic transmembrane proteins with six copper-binding motifs within the cytoplasmic N-terminal domain, eight transmembrane domains, and highly conserved catalytic domains. These proteins catalyze ATP-dependent copper transport across cell membranes for the metallation of many essential cuproenzymes, as well as for the removal of excess cellular copper to prevent copper toxicity. A key functional aspect of these copper transporters is their copper-responsive trafficking between the trans-Golgi network and the cell periphery. ATP7A- and ATP7B-deficiency, due to genetic mutation, underlie the inherited copper transport disorders, Menkes and Wilson diseases, respectively. Their importance in maintaining brain copper homeostasis is underscored by the severe neuropathological deficits in these disorders. Herein we will review and update our current knowledge of these copper transporters in the brain and the central nervous system, their distribution and regulation, their role in normal brain copper homeostasis, and how their absence or dysfunction contributes to disturbances in copper homeostasis and neurodegeneration.

No MeSH data available.


Related in: MedlinePlus