title: An atomic-level investigation of the disease-causing A629P mutant of the Menkes protein, ATP7A.
abstract: Menkes disease is a fatal disease that can be induced by various mutations in the ATP7A gene, leading to unpaired uptake of dietary copper. The ATP7A gene encodes a copper(I)-translocating ATPase. Here the disease-causing A629P mutation, which occurs in the last of the six copper(I)-binding soluble domains of the ATPase (hereafter MNK6), was investigated. To understand why this apparently minor amino acid replacement is pathogenic, the solution structures and dynamics on various time-scales of wild-type and A629P-MNK6 were determined both in the apo- and copper(I)-loaded forms. The interaction in vitro with the physiological ATP7A copper(I)-donor (HAH1) was additionally studied. The A629P mutation makes the protein beta-sheet more solvent accessible, possibly resulting in an enhanced susceptibility of ATP7A to proteolytic cleavage and/or in reduced capability of copper(I)-translocation. A small reduction of the affinity for copper(I) is also observed. Both effects could concur to pathogenicity.
authors.affiliation: Magnetic Resonance Center (CERM), University of Florence, Via L. Sacconi 6, 50019 Sesto Fiorentino, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Banci
authors.forename: Ivano
authors.initials: I
authors.lastname: Bertini
authors.forename: Francesca
authors.initials: F
authors.lastname: Cantini
authors.forename: Manuele
authors.initials: M
authors.lastname: Migliardi
authors.forename: Antonio
authors.initials: A
authors.lastname: Rosato
authors.forename: Shenlin
authors.initials: S
authors.lastname: Wang
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry* / Q000235:genetics; D019943:Amino Acid Substitution; D027682:Cation Transport Proteins / Q000737:chemistry* / Q000235:genetics; D003300:Copper / Q000737:chemistry; D000079922:Copper Transport Proteins; D000073840:Copper-Transporting ATPases; D018360:Crystallography, X-Ray; D006801:Humans; D007706:Menkes Kinky Hair Syndrome / Q000235:genetics*; D056511:Metallochaperones; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry; D009154:Mutation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry* / Q000235:genetics
chemical_list: C474500:ATOX1 protein, human; D027682:Cation Transport Proteins; D000079922:Copper Transport Proteins; D056511:Metallochaperones; D018832:Molecular Chaperones; D011993:Recombinant Fusion Proteins; D003300:Copper; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases