title: Menkes protein contributes to the function of peptidylglycine alpha-amidating monooxygenase.
abstract: Menkes protein (ATP7A) is a P-type ATPase involved in copper uptake and homeostasis. Disturbed copper homeostasis occurs in patients with Menkes disease, an X-linked disorder characterized by mental retardation, neurodegeneration, connective tissue disorders, and early childhood death. Mutations in ATP7A result in malfunction of copper-requiring enzymes, such as tyrosinase and copper/zinc superoxide dismutase. The first step of the two-step amidation reaction carried out by peptidylglycine alpha-amidating monooxygenase (PAM) also requires copper. We used tissue from wild-type rats and mice and an ATP7A-specific antibody to determine that ATP7A is expressed at high levels in tissues expressing high levels of PAM. ATP7A is largely localized to the trans Golgi network in pituitary endocrine cells. The Atp7a mouse, bearing a mutation in the Atp7a gene, is an excellent model system for examining the consequences of ATP7A malfunction. Despite normal levels of PAM protein, levels of several amidated peptides were reduced in pituitary and brain extracts of Atp7a mice, demonstrating that PAM function is compromised when ATP7A is inactive. Based on these results, we conclude that a reduction in the ability of PAM to produce bioactive end-products involved in neuronal growth and development could contribute to many of the biological effects associated with Menkes disease.
authors.affiliation: Department of Neuroscience,, University of Connecticut Health Center, Farmington, Connecticut 06030-3401, USA.
authors.forename: Tami C
authors.initials: TC
authors.lastname: Steveson
authors.forename: Giuseppe D
authors.initials: GD
authors.lastname: Ciccotosto
authors.forename: Xin-Ming
authors.initials: XM
authors.lastname: Ma
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Mueller
authors.forename: Richard E
authors.initials: RE
authors.lastname: Mains
authors.forename: Betty A
authors.initials: BA
authors.lastname: Eipper
mesh_terms: D000251:Adenosine Triphosphatases / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D000311:Adrenal Glands / Q000737:chemistry; D000324:Adrenocorticotropic Hormone / Q000032:analysis; D000818:Animals; D027682:Cation Transport Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D002540:Cerebral Cortex / Q000737:chemistry; D002766:Cholecystokinin / Q000032:analysis / Q000378:metabolism; D000073840:Copper-Transporting ATPases; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D006899:Mixed Function Oxygenases / Q000032:analysis / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000032:analysis / Q000378:metabolism*; D010902:Pituitary Gland / Q000737:chemistry; D010903:Pituitary Gland, Anterior / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000521:alpha-MSH / Q000032:analysis
chemical_list: C486201:Atp7a protein, mouse; D027682:Cation Transport Proteins; D009097:Multienzyme Complexes; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D000521:alpha-MSH; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D002766:Cholecystokinin; D006899:Mixed Function Oxygenases; C035189:peptidylglycine monooxygenase; D000251:Adenosine Triphosphatases; C486202:Atp7a protein, rat; D000073840:Copper-Transporting ATPases