Kinetic Analysis of the Interaction of the Copper Chaperone Atox1 with the Metal Binding Sites of the Menkes Protein

Strausak, Daniel; Howie, Michelle K.; Firth, Sonja; Schlicksupp, Andrea; Pipkorn, Rüdiger; Multhaup, Gerd; Mercer, Julian F. B.

doi:10.1074/jbc.m212437200

Cited by 62 publications

(66 citation statements)

References 49 publications

(55 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Domains 1 and 2 are separated by a 25 residue linker region, which could allow the two domains to orient properly for this type of coordination. This model could also explain surface plasmon resonance data indicating that MNK domains 1 and 2 have a lower affinity for Atox1 than the other domains (33). Although this finding may be because of the presence of a glutathione S-transferase tag (33), it could also result from the two domains coordinating a single Cu(I) ion.…”

Section: Discussionmentioning

confidence: 72%

“…Instead, only some of the domains might exchange copper with Atox1. Yeast two-hybrid data indicate that a polypeptide comprising domains 5 and 6, which are proposed to function in copper translocation (28), does not interact with Atox1 (32,33). Domains 5 and 6 could receive copper from domains 1-4, however.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, some of the domains may interact specifically with the copper chaperone Atox1. According to yeast two-hybrid assays using both WND (32) and MNK (33), Atox1 interacts most strongly with domains 1-4 and not at all with domains 5-6, although an interaction with MNK domains 5-6 has been detected by surface plasmon resonance (33). These interactions are metal-dependent and specific for copper.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Binding of Copper(I) by the Wilson Disease Protein and Its Copper Chaperone

Wernimont¹,

Yatsunyk

Rosenzweig

2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

The Wilson disease protein (WND) is a transport ATPase involved in copper delivery to the secretory pathway. Mutations in WND and its homolog, the Menkes protein, lead to genetic disorders of copper metabolism. 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 exact roles of these domains are not well established, but possible functions include exchanging copper with the metallochaperone Atox1 and mediating copper-responsive cellular relocalization. Although all six domains can bind copper, genetic and biochemical studies indicate that the domains are not functionally equivalent. One way the domains could be tuned to perform different functions is by having different affinities for Cu(I). We have used isothermal titration calorimetry to measure the association constant (K a ) and stoichiometry (n) values of Cu(I) binding to the WND metal-binding domains and to their metallochaperone Atox1. The association constants for both the chaperone and target domains are ϳ10 5 to 10 6 M ؊1 , suggesting that the handling of copper by Atox1 and copper transfer between Atox1 and WND are under kinetic rather than thermodynamic control. Although some differences in both n and K a values are observed for variant proteins containing less than the full complement of six metal-binding domains, the data for domains 1-6 were best fitted with a single site model. Thus, the individual functions of the six WND metal-binding domains are not conferred by different Cu(I) affinities but instead by fold and electrostatic surface properties.

show abstract

Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Binding of Copper(I) by the Wilson Disease Protein and Its Copper Chaperone

Wernimont¹,

Yatsunyk

Rosenzweig

2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…So far, two proteins are known to interact with the ATP7B N terminus. ATOX1 interacts with the N termini of both ATP7A and ATP7B in a copper-dependent manner to allow the delivery of copper to the ATPases (23)(24)(25)(26)(27). COMMD1, possibly involved in vesicular copper sequestration, also interacts with the N-terminal region of ATP7B but not ATP7A (29).…”

Section: Discussionmentioning

confidence: 99%

“…The copper chaperone ATOX1 interacts with the N termini of both ATP7A and ATP7B in a copper-dependent manner, and this interaction is essential for copper delivery to the secretory pathway (23)(24)(25)(26)(27). The recently discovered protein COMMD1 (MURR1), which is absent in Bedlington terriers suffering from copper toxicosis (28,29), interacts with the N terminus of ATP7B (29).…”

mentioning

confidence: 99%

Copper-dependent Interaction of Dynactin Subunit p62 with the N Terminus of ATP7B but Not ATP7A

Lim

Cater

Mercer

et al. 2006

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

The P-type ATPase affected in Wilson disease, ATP7B, is a key liver protein required to regulate and maintain copper homeostasis. When hepatocytes are exposed to elevated copper levels, ATP7B traffics from the trans-Golgi network toward the biliary canalicular membrane to excrete excess copper into bile. The N-terminal region of ATP7B contains six metal-binding sites (MBS), each with the copper-binding motif MXCXXC. These sites are required for the activity and copper-regulated intracellular redistribution of ATP7B. Two proteins are known to interact with the ATP7B N-terminal region: the copper chaperone ATOX1 that delivers copper to ATP7B, and COMMD1 (MURR1) that is potentially involved in vesicular copper sequestration. To identify additional proteins that interact with ATP7B and hence are involved in copper homeostasis, a yeast twohybrid approach was employed to screen a human liver cDNA library. The dynactin subunit p62 (dynactin 4; DCTN4) was identified as an interacting partner, and this interaction was confirmed by co-immunoprecipitation from mammalian cells. 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. The ATP7B/p62 interaction required copper, the metal-binding CXXC motifs, and the region between MBS 4 and MBS 6 of ATP7B. The p62 subunit did not interact with the related copper ATPase, ATP7A. We propose that the ATP7B interaction with p62 is a key component of the copper-induced trafficking pathway that delivers ATP7B to subapical vesicles of hepatocytes for the removal of excess copper into bile.

show abstract

Molecular Genetics of M enkes Disease

Comstra

Faúndez

2017

Encyclopedia of Life Sciences

View full text Add to dashboard Cite

Menkes disease is a recessive childhood disorder that results from systemic copper deficiency. This deficiency leads to loss of cuproenzyme function and subsequent defects in the hair, skin and vasculature. Patients also display severe neurodegeneration linked to copper deficiency in the brain. Menkes disease is monogenic and caused by loss‐of‐function mutations in the copper transporter ATP7A. ATP7A is responsible for the provision of copper to secretory cuproenzymes and for exporting excess copper out of the cell. Mutations in ATP7A associated with Menkes disease are heterogenous in both type and primary structure location, and no specific mutations are observed more frequently than others. Allelic variants that do not lead to complete loss of ATP7A function produce occipital horn syndrome and a form of spinal muscular atrophy. Key Concepts Menkes disease is an X‐linked recessive disorder with an occurrence of 1/40 000–1/360 000. Menkes disease presents 2–12 months after birth as hair, skin and joint abnormalities and later progresses to severe neurodegeneration. Loss‐of‐function mutations in the copper transporter ATP7A produce Menkes disease, and milder mutations produce occipital horn syndrome, characterised predominantly by connective tissue abnormalities, and a variant of spinal muscular atrophy. ATP7A is a Golgi‐localised protein that provides copper to secretory cuproenzymes. Under conditions of excess intracellular copper, ATP7A localises to the plasma membrane where it pumps excess copper out of the cell. Over 350 mutations have been identified in ATP7A that lead to Menkes disease. These mutations do not cluster to particular sequences in the gene and include a range of mutation types such as missense mutations, deletions and nonsense mutations, among others. Loss of ATP7A‐dependent cuproenzyme function accounts for many of the phenotypes associated with Menkes disease. For example, lack of copper incorporation into the melanin‐producing enzyme tyrosinase leads to hypopigmentation in patients. The pathogenesis of the severe neurodegeneration observed in Menkes patients is not well understood and is an active area of investigation.

show abstract

Kinetic Analysis of the Interaction of the Copper Chaperone Atox1 with the Metal Binding Sites of the Menkes Protein

Abstract: Excess copper is effluxed from mammalian cells by the

Cited by 62 publications

References 49 publications

Binding of Copper(I) by the Wilson Disease Protein and Its Copper Chaperone

Binding of Copper(I) by the Wilson Disease Protein and Its Copper Chaperone

Copper-dependent Interaction of Dynactin Subunit p62 with the N Terminus of ATP7B but Not ATP7A

Molecular Genetics of M enkes Disease

Contact Info

Product

Resources

About