Characterization of the Interaction between the Wilson and Menkes Disease Proteins and the Cytoplasmic Copper Chaperone, HAH1p

Larin, Dmitri; Mekios, Constantinos; Das, Kamna; Ross, Barbara; Yang, An‐Suei; Gilliam, T. Conrad

doi:10.1074/jbc.274.40.28497

Cited by 151 publications

(144 citation statements)

References 39 publications

(36 reference statements)

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“…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%

“…It is not known which WND domains receive copper directly from Atox1, although the strongest interaction by the yeast two-hybrid assay is observed for WD14 (32). If transfer is under thermodynamic control, the WND metal domains, or at least the subset that receives Cu(I) from Atox1, would be expected to have a higher affinity for Cu(I).…”

Section: Discussionmentioning

confidence: 99%

“…An approximate hierarchy of binding affinities is WD14 2 Ͼ WD34 Ն WD56 Ϸ (32). Of all the intervening sequences connecting the six metal-binding domains, the linker between domains 4 and 5 is the longest, consisting of 69 residues, and could cause tertiary structural differences between WD14 and WD16.…”

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%

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

Wernimont¹,

Yatsunyk

Rosenzweig

2004

Journal of Biological Chemistry

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Wernimont¹,

Yatsunyk

Rosenzweig

2004

Journal of Biological Chemistry

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“…ATP7A and 7B, which are both found in the trans-Golgi network, contain six MxCxxC metal binding domains (MBDs) at their amino termini and each MBD is capable of binding one atom of copper [53]. Antioxidant protein 1, or Atox1 (Atx1 in yeast) is a cytosolic copper chaperone responsible for the shuttling of Cu (I) to ATP7A and 7B [54][55][56][57]. Following binding to copper and under normal or low copper conditions, ATP7A and 7B translocate Cu (I) into the lumen of the secretory vesicles for integration into cuproenzymes such as ceruloplasmin and tyrosinase [58,59].…”

Section: Copper Metabolism In Eukaryotic Cellsmentioning

confidence: 99%