title: Enthalpy-entropy compensation at play in human copper ion transfer.
abstract: Copper (Cu) is an essential trace element but toxic in free form. After cell uptake, Cu is transferred, via direct protein-protein interactions, from the chaperone Atox1 to the Wilson disease protein (WD) for incorporation into Cu-dependent enzymes. Cu binds to a conserved C(1)XXC(2) motif in the chaperone as well as in each of the cytoplasmic metal-binding domains of WD. Here, we dissect mechanism and thermodynamics of Cu transfer from Atox1 to the fourth metal binding domain of WD. Using chromatography and calorimetry together with single Cys-to-Ala variants, we demonstrate that Cu-dependent protein heterocomplexes require the presence of C(1) but not C(2). Comparison of thermodynamic parameters for mutant versus wild type reactions reveals that the wild type reaction involves strong entropy-enthalpy compensation. This property is explained by a dynamic inter-conversion of Cu-Cys coordinations in the wild type ensemble and may provide functional advantage by protecting against Cu mis-ligation and bypassing enthalpic traps.
authors.affiliation: Department of Chemistry, Umeå University, 901 87 Umeå, Sweden.
authors.forename: Moritz S
authors.initials: MS
authors.lastname: Niemiec
authors.affiliation: Department of Chemistry, Umeå University, 901 87 Umeå, Sweden.
authors.forename: Artur P G
authors.initials: AP
authors.lastname: Dingeldein
authors.affiliation: Department of Chemistry, Umeå University, 901 87 Umeå, Sweden.
authors.forename: Pernilla
authors.initials: P
authors.lastname: Wittung-Stafshede
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000378:metabolism; D020816:Amino Acid Motifs; D002151:Calorimetry; D027682:Cation Transport Proteins / Q000737:chemistry / Q000378:metabolism; D002850:Chromatography, Gel; D003300:Copper / Q000737:chemistry / Q000378:metabolism*; D000079922:Copper Transport Proteins; D000073840:Copper-Transporting ATPases; D019277:Entropy; D006801:Humans; D007477:Ions / Q000737:chemistry; D056511:Metallochaperones / Q000737:chemistry / Q000378:metabolism; D018832:Molecular Chaperones; D017434:Protein Structure, Tertiary
chemical_list: C474500:ATOX1 protein, human; D027682:Cation Transport Proteins; D000079922:Copper Transport Proteins; D007477:Ions; D056511:Metallochaperones; D018832:Molecular Chaperones; D003300:Copper; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases