Falcon deep research report for human ATP7B
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ATP7B is a P1B-type ATP-dependent Cu(I) transporter with core functions in TGN copper loading and copper-induced vesicular export.
"ATP7B encodes the Wilson disease copper transporter, a **P1B-type (P-type) Cu(I)-transporting ATPase** whose well-supported GO-relevant biology centers on: (i) **ATP-driven Cu(I) export from the cytosol into the trans-Golgi network (TGN) lumen** for metallation of secretory cuproproteins, and (ii) **copper-induced trafficking** to post-Golgi vesicles/pericanalicular compartments to enable **cellular copper detoxification and biliary copper excretion** in hepatocytes."
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ATOX1-mediated copper transfer is the informative protein interaction for ATP7B.
"The cytosolic copper chaperone **ATOX1** delivers Cu(I) to ATP7B by forming **transient Cu-bridged protein–protein complexes**, stabilized largely by the copper-coordinating cysteines, transferring Cu(I) to ATP7B’s N-terminal MBDs and (directly or indirectly) onward to the transmembrane transport site."
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ATP7B plasma membrane and late endosome annotations require caution.
"The exact identity of the vesicular carriers and whether ATP7B transiently resides at the canalicular membrane remain debated."
Gene Ontology annotation through association of InterPro records with GO terms
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Gene Ontology annotation based on curation of immunofluorescence data
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
Electronic Gene Ontology annotations created by ARBA machine learning models
Combined Automated Annotation using Multiple IEA Methods
The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene.
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Original identification of ATP7B as the Wilson disease gene with 76% amino acid homology to ATP7A (Menkes disease gene).
"The predicted functional properties of the pWD gene together with its strong homology to Mc1, genetic mapping data and identification of four independent disease-specific mutations, provide convincing evidence that pWD is the Wilson disease gene."
Functional characterization of missense mutations in ATP7B: Wilson disease mutation or normal variant?
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CPC motif is essential for ATP7B copper transport activity.
"Mutation of the CPC motif resulted in a nonfunctional protein, which demonstrates that this motif is essential for copper transport by ATP7B."
Metallochaperone Atox1 transfers copper to the NH2-terminal domain of the Wilson's disease protein and regulates its catalytic activity.
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ATOX1 transfers copper to ATP7B and stimulates its catalytic activity.
"We demonstrate that Atox1 transfers copper to the purified amino-terminal domain of WNDP (N-WNDP) in a dose-dependent and saturable manner."
Copper-induced trafficking of the cU-ATPases: a key mechanism for copper homeostasis.
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Copper-induced trafficking of Cu-ATPases is a key homeostatic mechanism.
"In cells cultured in low copper concentration MNK and WND localize to the transGolgi network but in high copper relocalize either to the plasma membrane (MNK) or a vesicular compartment (WND)."
Functional properties of the human copper-transporting ATPase ATP7B (the Wilson's disease protein) and regulation by metallochaperone Atox1.
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ATP7B catalytic activity is stimulated by copper and ATOX1.
"Wilson's disease protein (WNDP) is a copper-transporting P(1)-type ATPase which plays a key role in normal distribution of copper in a number of tissues, particularly in the liver and the brain."
The copper toxicosis gene product Murr1 directly interacts with the Wilson disease protein.
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COMMD1 (Murr1) directly interacts with ATP7B.
"the Wilson disease protein directly interacts with the human homologue of Murr1 in vitro and in vivo and that this interaction is mediated via the copper binding, amino terminus of this ATPase."
Binding of copper(I) by the Wilson disease protein and its copper chaperone.
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ATP7B binds Cu(I) via six N-terminal HMA domains with CXXC motifs.
"The WND and Menkes proteins are distinguished from other P-type ATPases by the presence of six soluble N-terminal metal-binding domains containing a conserved CXXC metal-binding motif."
The distinct functional properties of the nucleotide-binding domain of ATP7B, the human copper-transporting ATPase: analysis of the Wilson disease mutations E1064A, H1069Q, R1151H, and C1104F.
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Wilson disease mutations affect ATP binding and catalytic activity.
"Mutations of the invariant WNDP residues E1064A and H1069Q drastically reduce nucleotide affinities, pointing to the likely role of these residues in nucleotide coordination."
Signals regulating trafficking of Menkes (MNK; ATP7A) copper-translocating P-type ATPase in polarized MDCK cells.
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This paper is about ATP7A (Menkes), NOT ATP7B. Annotations attributed to ATP7B from this paper are mis-annotations.
"we demonstrate that MNK relocalizes from the Golgi to the basolateral (BL) membrane under elevated copper conditions."
The Wilson disease protein ATP7B resides in the late endosomes with Rab7 and the Niemann-Pick C1 protein.
ATP7B mediates vesicular sequestration of copper: insight into biliary copper excretion.
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ATP7B mediates copper excretion via vesicular sequestration, not direct plasma membrane transport.
"In HepG2 cells, elevated copper levels stimulated trafficking of ATP7B to pericanalicular vesicles and not to the canalicular membrane as previously reported."
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Vesicles, not plasma membrane, are the final trafficking destination for ATP7B.
"Mutation of an endocytic retrieval signal in ATP7B caused the protein to constitutively localize to vesicles and not to the plasma membrane, suggesting that a vesicular compartment(s) is the final trafficking destination for ATP7B."
Copper-dependent interaction of dynactin subunit p62 with the N terminus of ATP7B but not ATP7A.
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DCTN4 (p62) interacts specifically with ATP7B N-terminus in a copper-dependent manner.
"The dynactin complex binds cargo, such as vesicles and organelles, to cytoplasmic dynein for retrograde microtubule-mediated trafficking and could feasibly be involved in the copper-regulated trafficking of ATP7B."
Solution structure of the N-domain of Wilson disease protein: distinct nucleotide-binding environment and effects of disease mutations.
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NMR structure reveals distinct nucleotide-binding environment in ATP7B N-domain.
"the nucleotide coordination environment of ATP7B within this fold is different. The residues H1069, G1099, G1101, I1102, G1149, and N1150 conserved in the P(1B)-ATPase subfamily contribute to ATP binding."
A new hepatocytic isoform of PLZF lacking the BTB domain interacts with ATP7B, the Wilson disease protein, and positively regulates ERK signal transduction.
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Hepatocytic ZBTB16/PLZF isoform interacts with ATP7B C-terminus.
"These data suggest the existence of a mechanism that regulates ERK signaling via the C-terminus of ATP7B and the ATP7B-interacting hepatocytic PLZF."
Copper-dependent interaction of glutaredoxin with the N termini of the copper-ATPases (ATP7A and ATP7B) defective in Menkes and Wilson diseases.
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GRX1 interacts with ATP7B N-terminus in a copper-dependent manner.
"We propose that GRX1 is essential for ATPase function and catalyses either the reduction of intramolecular disulphide bonds or the deglutathionylation of the cysteine residues within the CxxC motifs to facilitate copper-binding for subsequent transport."
Copper binding to the N-terminal metal-binding sites or the CPC motif is not essential for copper-induced trafficking of the human Wilson protein (ATP7B).
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ATP7B copper-induced trafficking is coupled to catalytic cycle, not direct copper binding.
"ATP7B trafficking is regulated with its copper-translocation cycle, with cytosolic vesicular localization associated with the acyl-phosphate intermediate."
Distinct Wilson's disease mutations in ATP7B are associated with enhanced binding to COMMD1 and reduced stability of ATP7B.
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Wilson disease mutations enhance COMMD1 binding and reduce ATP7B stability.
"Four WD patient-derived mutations in this region of ATP7B significantly increased its binding to COMMD1. Two of these mutations also resulted in mislocalization and increased degradation rate of ATP7B."
Defining the membrane proteome of NK cells.
Diverse functional properties of Wilson disease ATP7B variants.
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Comprehensive functional characterization of 27 Wilson disease variants.
"Properties of ATP7B variants with pathogenic amino-acid substitution varied greatly even if substitutions were in the same functional domain. Some variants had complete loss of catalytic and transport activity, whereas others lost transport activity but retained phosphor-intermediate formation or had partial losses of activity."
Functional characterization of new mutations in Wilson disease gene (ATP7B) using the yeast model.
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Yeast complementation demonstrates ATP7B copper transport activity.
"Expression of human wild type ATP7B gene in ccc2Δ mutant yeast restored the growth deficiency and copper transport activity; however, expression of the mutant forms did not restore the copper transport functions and only partially supported the cell growth."
Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
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ATP7B detected in high-throughput mitochondrial proteomics.
"We classified >8,000 proteins in mitochondrial preparations of human cells and defined a mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP)."
Ion transport by P-type ATPases
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ATP7B is part of the P-type ATPase ion transport pathway.
"The P-type ATPases (E1-E2 ATPases) are a large group of evolutionarily related ion pumps that are found in bacteria, archaea and eukaryotes."
ATP7B transports cytosolic Cu1+ to Golgi lumen
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ATP7B transports Cu(I) from cytosol to Golgi lumen coupled to ATP hydrolysis.
"ATP7B resides on the trans-Golgi membrane where it it thought to sequester copper from the cytosol into the golgi (Yang et al, 1997)."