The Role of the Invariant His-1069 in Folding and Function of the Wilson's Disease Protein, the Human Copper-transporting ATPase ATP7B

Tsivkovskii, Ruslan; Efremov, Roman G.; Lutsenko, Svetlana

doi:10.1074/jbc.m300034200

Cited by 68 publications

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References 22 publications

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“…All patients had p.H1069Q in one ATP7B allele and an uncharacterized missense mutation, c.1958C > A [p.S653Y] in the second allele. Previous studies have demonstrated that the H1069Q mutation results in significant mislocalization, instability (8,18), and low residual activity of ATP7B protein (9), which may account for some active copper-loaded CPN (holo-CP). It is also known that heterozygous individuals with one wild-type and one p.H1069Q allele do not have WD (Table 1) (19), indicating that in patients with the p.H1069Q/S653Y genotype, ATP7B S653Y is not functionally competent to prevent WD.…”

Section: Resultsmentioning

confidence: 99%

“…Presently, about two dozen mutations found in WD patients have been characterized in detail (4)(5)(6)(7). These studies revealed that the most common effect of a WD mutation is ATP7B misfolding, which results in retention of newly synthesized ATP7B in the endoplasmic reticulum (ER), a marked decrease in protein stability, and loss of Cu(I)-transport activity (8,9). Destabilization and inactivation of ATP7B explain the common phenotypic manifestations in WD, such as impaired copper export from the liver and the lack of copper incorporation into secreted cuproenzymes, such as ceruloplasmin (CPN).…”

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confidence: 99%

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Distinct phenotype of a Wilson disease mutation reveals a novel trafficking determinant in the copper transporter ATP7B

Braiterman¹,

Murthy²,

Jayakanthan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Wilson disease (WD) is a monogenic autosomal-recessive disorder of copper accumulation that leads to liver failure and/or neurological deficits. WD is caused by mutations in ATP7B, a transporter that loads Cu(I) onto newly synthesized cupro-enzymes in the trans-Golgi network (TGN) and exports excess copper out of cells by trafficking from the TGN to the plasma membrane. To date, most WD mutations have been shown to disrupt ATP7B activity and/or stability. Using a multidisciplinary approach, including clinical analysis of patients, cell-based assays, and computational studies, we characterized a patient mutation, ATP7B S653Y , which is stable, does not disrupt Cu(I) transport, yet renders the protein unable to exit the TGN. Bulky or charged substitutions at position 653 mimic the phenotype of the patient mutation. Molecular modeling and dynamic simulation suggest that the S653Y mutation induces local distortions within the transmembrane (TM) domain 1 and alter TM1 interaction with TM2. S653Y abolishes the trafficking-stimulating effects of a secondary mutation in the N-terminal apical targeting domain. This result indicates a role for TM1/ TM2 in regulating conformations of cytosolic domains involved in ATP7B trafficking. Taken together, our experiments revealed an unexpected role for TM1/TM2 in copper-regulated trafficking of ATP7B and defined a unique class of WD mutants that are transport-competent but trafficking-defective. Understanding the precise consequences of WD-causing mutations will facilitate the development of advanced mutation-specific therapies.ceruloplasmin | interdomain interactions | molecular dynamics

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Distinct phenotype of a Wilson disease mutation reveals a novel trafficking determinant in the copper transporter ATP7B

Braiterman¹,

Murthy²,

Jayakanthan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Copper is an important co-factor for many enzymes involved in diverse cellular processes, such as radical detoxification, oxidative phosphorylation and iron metabolism (Tsivkovskii et al, 2003). The two oxidation states of copper (Cu + and Cu 2+ ) and its relatively broad redox potential when bound to protein (200-800 mV) make it important to metalloenzymes in many redox-driven reactions (Solioz & Stoyanov, 2003).…”

Section: Introductionmentioning

confidence: 99%

Molecular insight into extreme copper resistance in the extremophilic archaeon ‘Ferroplasma acidarmanus’ Fer1

et al. 2005

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‘Ferroplasma acidarmanus’ strain Fer1 is an extremely acidophilic archaeon involved in the genesis of acid mine drainage, and was isolated from copper-contaminated mine solutions at Iron Mountain, CA, USA. Here, the initial proteomic and molecular investigation of Cu2+ resistance in this archaeon is presented. Analysis of Cu2+ toxicity via batch growth experiments and inhibition of oxygen uptake in the presence of ferrous iron demonstrated that Fer1 can grow and respire in the presence of 20 g Cu2+ l−1. The Fer1 copper resistance (cop) loci [originally detected by Ettema, T. J. G., Huynen, M. A., de Vos, W. M. & van der Oost, J. Trends Biochem Sci 28, 170–173 (2003)] include genes encoding a putative transcriptional regulator (copY), a putative metal-binding chaperone (copZ) and a putative copper-transporting P-type ATPase (copB). Transcription analyses demonstrated that copZ and copB are co-transcribed, and transcript levels were increased significantly in response to exposure to high levels of Cu2+, suggesting that the transport system is operating for copper efflux. Proteomic analysis of Fer1 cells exposed to Cu2+ revealed the induction of stress proteins associated with protein folding and DNA repair (including RadA, thermosome and DnaK homologues), suggesting that ‘Ferroplasma acidarmanus’ Fer1 uses multiple mechanisms for resistance to high levels of copper.

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“…In vitro, the H1069Q substitution decreases the affinity for ATP and prevents the formation of a catalytic phosphointermediate (3,4,9,15). In the cell, this mutation is associated with mistargeting of ATP7B.…”

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“…Moreover, the H1069Q mutant has a decreased half-life compared with the wild-type ATP7B (17). The reasons for the retention of H1069Q mutant in the ER and its shorter half-life are not clear because the mutation does not cause noticeable structural defects in either the N-domain or the full-length ATP7B (4,15). Similarly, in archaean CopA, an equivalent mutation was shown to change the coordination mode of ATP without affecting protein structure (8).…”

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Difference in Stability of the N-domain Underlies Distinct Intracellular Properties of the E1064A and H1069Q Mutants of Copper-transporting ATPase ATP7B

Dmitriev

Bhattacharjee

Nokhrin

et al. 2011

Journal of Biological Chemistry

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Wilson disease (WD) is a disorder of copper metabolism caused by mutations in the Cu-transporting ATPase ATP7B. WD is characterized by significant phenotypic variability, the molecular basis of which is poorly understood. The E1064A mutation in the N-domain of ATP7B was previously shown to disrupt ATP binding. We have now determined, by NMR, the structure of the N-domain containing this mutation and compared properties of E1064A and H1069Q, another mutant with impaired ATP binding. The E1064A mutation does not change the overall fold of the N-domain. However, the position of the ␣1,␣2-helical hairpin (␣-HH) that houses Glu 1064 and His 1069 is altered. The ␣-HH movement produces a more open structure compared with the wild-type ATP-bound form and misaligns ATP coordinating residues, thus explaining complete loss of ATP binding. In the cell, neither the stability nor targeting of ATP7B-E1064A to the trans-Golgi network differs significantly from the wild type. This is in a contrast to the H1069Q mutation within the same ␣-HH, which greatly destabilizes protein both in vitro and in cells. The difference between two mutants can be linked to a lower stability of the ␣-HH in the H1069Q variant at the physiological temperature. We conclude that the structural stability of the N-domain rather than the loss of ATP binding plays a defining role in the ability of ATP7B to reach the trans-Golgi network, thus contributing to phenotypic variability in WD.The human copper-transporting ATPase ATP7B regulates copper levels in the cytosol and within the secretory pathway (1). Genetic mutations that disrupt the transport function of ATP7B lead to Wilson disease (WD), 4 a severe metabolic disorder associated with copper accumulation in the liver, brain, and other tissues (2). The WD phenotypes are rather diverse. The disease is characterized by significant variability in the age of onset, severity, and manifestations, which include hepatic, neurological, and psychiatric symptoms. More than 350 WDcausing mutations have been described. The majority of these mutations are single base pair substitutions that do not eliminate synthesis of the full-length ATP7B. Despite considerable effort, no strong correlations have been observed between specific mutations and the disease phenotype, necessitating better understanding of the effects that mutations have on ATP7B structure, function, and intracellular behavior.ATP7B transports copper from the cytosol across cellular membranes using the energy of ATP hydrolysis. ATP binds to the cytosolic ATP-hydrolyzing domain, which consists of the N-and P-domains. The bulk of the ATP molecule is bound to the N-domain (3, 4), whereas the ␥-phosphate extends to the P-domain to transiently phosphorylate the invariant aspartate residue Asp 1027 . The structure of the N-domain has been solved for human ATP7B (4) and several orthologs (5-8). These studies have identified invariant residues contributing to the ATP binding pocket. In ATP7B, these residues are Glu 1064 , Glu 1068 , His 1069 , Gly 1101 , Asn 115...

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The Role of the Invariant His-1069 in Folding and Function of the Wilson's Disease Protein, the Human Copper-transporting ATPase ATP7B

Cited by 68 publications

References 22 publications

Distinct phenotype of a Wilson disease mutation reveals a novel trafficking determinant in the copper transporter ATP7B

Distinct phenotype of a Wilson disease mutation reveals a novel trafficking determinant in the copper transporter ATP7B

Molecular insight into extreme copper resistance in the extremophilic archaeon ‘Ferroplasma acidarmanus’ Fer1

Difference in Stability of the N-domain Underlies Distinct Intracellular Properties of the E1064A and H1069Q Mutants of Copper-transporting ATPase ATP7B

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