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The lumenal loop M672-P707 of the Menkes protein (ATP7A) transfers copper to peptidylglycine monooxygenase

Journal Article · · Journal of the American Chemical Society
DOI:https://doi.org/10.1021/ja301221s· OSTI ID:1040806
 [1];  [2];  [3];  [4];  [5];  [5];  [3]
  1. Oregon Health & Sciences University
  2. Los Alamos National Laboratory
  3. Oregon Health & Science University
  4. Illinois EPR Center
  5. Johns Hopkins University
+ Show Author Affiliations
Copper transfer to cuproproteins located in vesicular compartments of the secretory pathway depends on activity of the copper translocating ATPase (ATP7A or ATP7B) but the mechanism of transfer is largely unexplored. Copper-ATPase ATP7A is unique in having a sequence rich in histidine and methionine residues located on the lumenal side of the membrane. The corresponding fragment binds Cu(I) when expressed as a chimera with a scaffold protein, and mutations or deletions of His and/or Met residues in its sequence inhibit dephosphorylation of the ATPase, a catalytic step associated with copper release. Here we present evidence for a potential role of this lumenal region of ATP7A in copper transfer to cuproenzymes. Both Cu(II) and Cu(I) forms were investigated since the form in which copper is transferred to acceptor proteins is currently unknown. Analysis of Cu(II) using EPR demonstrated that at Cu:P ratios below 1:1, 15N-substituted protein had Cu(II) bound by 4 His residues, but this coordination changed as the Cu(II) to protein ratio increased towards 2:1. XAS confirmed this coordination via analysis of the intensity of outer-shell scattering from imidazole residues. The Cu(II) complexes could be reduced to their Cu(I) counterparts by ascorbate, but here again, as shown by EXAFS and XANES spectroscopy, the coordination was dependent on copper loading. At low copper Cu(I) was bound by a mixed ligand set of His + Met while at higher ratios His coordination predominated. The copper-loaded loop was able to transfer either Cu(II) or Cu(I) to peptidylglycine monooxygenase in the presence of chelating resin, generating catalytically active enzyme in a process that appeared to involve direct interaction between the two partners. The variation of coordination with copper loading suggests copper-dependent conformational change which in turn could act as a signal for regulating copper release by the ATPase pump.
Research Organization:
Los Alamos National Laboratory (LANL)
Sponsoring Organization:
Work performed elsewhere
DOE Contract Number:
AC52-06NA25396
OSTI ID:
1040806
Report Number(s):
LA-UR-12-21360
Journal Information:
Journal of the American Chemical Society, Journal Name: Journal of the American Chemical Society; ISSN JACSAT; ISSN 0002-7863
Country of Publication:
United States
Language:
English

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
ATP-ASE
CHIMERAS
COMPARTMENTS
CONFORMATIONAL CHANGES
COPPER
ENZYMES
HISTIDINE
IMIDAZOLES
METHIONINE
MUTATIONS
PROTEINS
RESIDUES
SCATTERING
SPECTROSCOPY