An NMR Study of the Interaction of the N-terminal Cytoplasmic Tail of the Wilson Disease Protein with Copper(I)-HAH1

Abstract

ATP7B is a human P1B-type ATPase that has a crucial role in maintaining copper(I) homeostasis. Mutations in the corresponding gene are the cause of Wilson disease. Among its various distinguishing features is a long (∼630 amino acids) N-terminal cytosolic tail containing six domains that are individually folded and capable of binding one copper(I) ion each. We expressed the entire tail as a single construct in Escherichia coli and investigated its interaction with its copper chaperone (i.e. HAH1) by solution NMR spectroscopy. We observed that all six of the metal-binding domains were metallated by Cu(I)-HAH1, with the first, the second, and the fourth domains forming an adduct with it. This behavior is different from that of the highly similar human ATPase ATP7A, in which only two domains form such an adduct. The distinct behaviors of the different domains were analyzed in terms of the energetics of Cu(I) transfer, hinting at a specific role of the interaction with copper(I)-HAH1 in the overall functional process. ATP7B is a human P1B-type ATPase that has a crucial role in maintaining copper(I) homeostasis. Mutations in the corresponding gene are the cause of Wilson disease. Among its various distinguishing features is a long (∼630 amino acids) N-terminal cytosolic tail containing six domains that are individually folded and capable of binding one copper(I) ion each. We expressed the entire tail as a single construct in Escherichia coli and investigated its interaction with its copper chaperone (i.e. HAH1) by solution NMR spectroscopy. We observed that all six of the metal-binding domains were metallated by Cu(I)-HAH1, with the first, the second, and the fourth domains forming an adduct with it. This behavior is different from that of the highly similar human ATPase ATP7A, in which only two domains form such an adduct. The distinct behaviors of the different domains were analyzed in terms of the energetics of Cu(I) transfer, hinting at a specific role of the interaction with copper(I)-HAH1 in the overall functional process. Human ATP7B is a P1B-type ATPase that, like the other human copper(I)-transporting ATPase, ATP7A, can translocate copper(I) to the trans-Golgi network, where the metal is incorporated into copper-dependent enzymes. Copper stimulation results in the redistribution of both ATP7A and ATP7B to the plasma membrane through intracellular vesicles in order to export excess copper out of the cytosol (1Petris M.J. Mercer J.F. Culvenor J.G. Lockhart P. Camakaris J. EMBO J. 1996; 15: 6084-6095Crossref PubMed Scopus (538) Google Scholar, 2Schaefer M. Hopkins R.G. Failla M.L. Gitlin J.D. Am. J. 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Cantini F. E. Rosato A. Biochemistry. 2004; 43: PubMed Scopus Google Scholar). copper(I)-HAH1 and in the NMR the same for L. Bertini I. Cantini F. Della Malva N. Migliardi M. Rosato A. J. Biol. Chem. 2007; 282: 23140-23146Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). NMR were at of and all with of were through NMR J. Fairbrother W.J. NMR and Scholar). of with copper(I)-HAH1 were through quantum P. E. B. J. Am. Chem. 2005; Scholar). The of copper(I)-HAH1 in the presence of investigated through the of rates R. Nat. Struct. Biol. 2000; PubMed Scopus Google Scholar). one to NMR the NMR is in the of the NMR were with the R. The Scholar). The amino acids of WLN with the the entire cytosolic tail and in the six were expressed in E. coli as a single the in the and its by NMR spectroscopy. only at in the were a of The of the are to the presence of long between the various which to of one We from all six MBDs the both for the and copper(I) are in and the other of the and from the domains and domains and and domains and The present that for L. Bertini I. Cantini F. Della Malva N. Migliardi M. Rosato A. J. Biol. Chem. 2007; 282: 23140-23146Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). a copper(I) the The of metallated were used to metal from copper(I)-HAH1 to the various MBDs of with the major of the of the interaction between and This investigated by the to with only one of the two proteins in that only its in The The interaction with copper(I)-HAH1 a of the of the from the of domains and of the Instead, for domains and observed or intermediate with the in the features to the same the and The the various metal-binding domains instead through the of the and sixth domains of by an of a of the of and of in the presence of and of MBDs are in of with copper(I)-HAH1 from the of in the of between and in the presence of and of in the of between and in the presence of of are through the A. Biochemistry. 1997; PubMed Scopus Google Scholar), which is from the and and between corresponding in the two through The the that The of the six MBDs the sequence are by The of domains and in a single and the corresponding a in the that the and The observed for corresponding in these domains were similar the The of domains and to both the metal-binding and the between the and the fourth of domain is at the of the metal-bridged adduct by the yeast proteins L. Bertini I. Cantini F. L. N. R. Rosato A. P. Nat. Chem. Biol. 2006; PubMed Scopus Google Scholar). of the of the MBD of domain in which to from the copper(I) form domains and the were to the metal-binding and by interaction with the The of the form with a similar the of all of the corresponding of the copper(I) form at the same the from and in and were essentially metallated at the of the at copper(I)-HAH1 with it observed that the interaction a in the of various in the essentially all of the of the the metal-binding order to the of the of an adduct and the for in solution of copper(I)-HAH1 and in the presence of of the of in the to from of the J. Banci L. Bertini I. Cantini F. E. Rosato A. Biochemistry. 2004; 43: PubMed Scopus Google Scholar) which from the of rates and the of This in the of that the an adduct with one or of the domains of The overall behavior for a between the from domains and the one and and the all of these and the of the similar behavior of other such as human Menkes and yeast it can that all of the six domains of were metallated by the metal-bridged with domains and at levels by NMR which were in the NMR with the single and the copper(I) form of domains and with the form in an intermediate to domains and were metallated by copper(I)-HAH1 or an copper the interaction of copper(I)-HAH1 with a of where the metal-binding of domains and to these domains to bind The of essentially to that of the same with the of the amino acids and of in the of copper(I)-HAH1 to the observed that domains and copper(I) from the same that were observed in The of of the metallated domains were in with the form the the of from domains and that were with the the construct with the behavior of its six MBDs the NMR of the from domains (the first, second, and a of that the Instead, for the other domains (the and the of copper(I)-HAH1 to of in or intermediate with the form has in the for that the present behavior of the of the amino acids in domains and results from the of an adduct with D. 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Biol. 2006; PubMed Scopus Google Scholar), where the metal ion the proteins in the as it is by two of one and one of the the yeast are two of the in L. Bertini I. Cantini F. L. N. R. Rosato A. P. Nat. Chem. Biol. 2006; PubMed Scopus Google Scholar). The two in the of the the two the form with the ATPase two L. Bertini I. Cantini F. L. N. R. Rosato A. P. Nat. Chem. Biol. 2006; PubMed Scopus Google Scholar). is in with a of the of and various (32Larin D. Mekios C. Das K. Ross B. Yang A.S. Gilliam C.T. J. Biol. Chem. 1999; 274: 28497-28504Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar, 33Strausak D. Howie M.K. Firth S.D. A. R. G. Mercer J.F. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar, M. Biochem. Biophys. Res. Commun. 2004; PubMed Scopus Google Scholar, L. Bertini I. Cantini F. L. N. R. Rosato A. P. Nat. Chem. Biol. 2006; PubMed Scopus Google the the various investigated to a of the and of the process. the affinity for copper(I) of the metallochaperone and of the MBD of the Ccc2 ATPase is the same (31Huffman D.L. O'Halloran T.V. J. Biol. Chem. 2000; 275: 18611-18614Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar). is with a adduct of the F. Banci L. Bertini I. Cantini F. Ciofi-Baffoni S. Huffman D.L. O'Halloran T.V. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). The adduct is in with the The various MBDs of MNK L. Bertini I. Cantini F. Migliardi M. Rosato A. Wang S. J. Mol. Biol. 2005; 352: 409-417Crossref PubMed Scopus (33) Google Scholar, L. Bertini I. C. Ciofi-Baffoni S. N. Rosato A. J. 2005; 272: PubMed Scopus Google Scholar) and WLN (29Yatsunyk L.A. Rosenzweig A.C. J. Biol. Chem. 2007; 282: 8622-8631Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar) have a affinity for copper(I) HAH1. MBDs form an adduct at with for the other the complex is and only the metallated form can only two domains (the and the form an adduct L. Bertini I. Cantini F. Della Malva N. Migliardi M. Rosato A. J. Biol. Chem. 2007; 282: 23140-23146Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar) at similar the MBD of MNK is metallated by copper(I)-HAH1 the of of a adduct. This behavior is observed both in the of the entire tail L. Bertini I. Cantini F. Della Malva N. Migliardi M. Rosato A. J. Biol. Chem. 2007; 282: 23140-23146Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar) and for the domain L. Bertini I. C. Ciofi-Baffoni S. N. Rosato A. J. 2005; 272: PubMed Scopus Google Scholar). The different behaviors to different for the copper which are in for the of the has a only the is in MNK and WLN the complex is similar to the the both the of of the intermediate adduct is its is to that of the of is of the affinity for copper(I) of the metallochaperone and the the adduct is it is in with the proteins, the other for MBDs that form of the between the and copper(I) is of the presence of HAH1. The as a in the between the two of the metal-binding domains The N-terminal tail of P1B-type ATPases have a role in the enzyme activity trafficking (17Rice W.J. Kovashilin A. Stokes D.L. Biochem. Biophys. Res. Commun. 2006; 348: 124-131Crossref PubMed Scopus (19) Google Scholar, M.A. La Fontaine S. Mercer J.F. Biochem. J. 2007; 401: 143-153Crossref PubMed Scopus (49) Google Scholar, 21Cater M.A. Forbes J.R. La Fontaine S. Cox D. Mercer J.F. Biochem. J. 2004; 380: 805-813Crossref PubMed Scopus (92) Google Scholar). the tail have an role in the of copper(I) Y. Hirata A. Toyoshima C. 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A. 2003; PubMed Scopus Google Scholar). the to the of the adduct with the metallochaperone or to the of copper(I) is the one of these it can the of the ATPase that to The is and the The in the is the relatively for the observed that the at The to the MBD or to the two MBDs to the transmembrane of MNK and WLN as a role different the N-terminal four domains R. Lutsenko S. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, J.F. N. J. Strausak D. 2003; PubMed Scopus Google Scholar). it is that for both human proteins, the fifth and sixth MBDs are metallated by the metallochaperone forming of The of these two domains the of with other metal-binding domains the cytosolic tail, as by for both MNK L. Bertini I. Cantini F. Della Malva N. Migliardi M. Rosato A. J. Biol. Chem. 2007; 282: 23140-23146Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar) and WLN This is at with observed for yeast This ATPase has only two of which at one a complex with the four domains in WLN and two in MNK can form of an adduct. The are the of of which the of the with copper(I)-HAH1 in This to tuning the of the activity trafficking of the for WLN and a to in the tissues where are R. Lutsenko S. J. 2007; 39: PubMed Scopus (86) Google Scholar). We Huffman for with