Sequence variation in the ATP-binding domain of the Wilson disease transporter, ATP7B, affects copper transport in a yeast model system

Human Mutation
Gloria HsiDiane W Cox

Abstract

ATP7B is a copper transporting P-type ATPase defective in the autosomal recessive copper storage disorder, Wilson disease (WND). Functional assessment of variants helps to distinguish normal from disease-causing variants and provides information on important amino acid residues. A total of 11 missense variants of ATP7B, originally identified in WND patients, were examined for their capacity to functionally complement a yeast mutant strain in which the yeast gene ortholog, CCC2, was disrupted. Solution structures of ATP7B domains were used to predict the effects of each variant on ATP7B structure. Three variants lie within the copper-binding domain and eight within the ATP-binding domain of ATP7B. All three ATP7B variants within the copper-binding domain and four within the ATP-binding domain showed full complementation of the yeast ccc2 phenotype. For the remaining four located in the ATP-binding domain, p.Glu1064Lys and p.Val1106Asp were unable to complement the yeast ccc2 high-affinity iron uptake deficiency phenotype, apparently due to mislocalization and/or change in conformation of the variant protein. p.Leu1083Phe exhibited a temperature-sensitive phenotype with partial complementation at 30 degrees C and a severe deficit...Continue Reading

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Citations

Dec 6, 2012·Translational Neurodegeneration·Qin-Yun Dong, Zhi-Ying Wu
Apr 8, 2014·Proceedings of the National Academy of Sciences of the United States of America·Lelita T BraitermanAnn L Hubbard
Feb 24, 2009·La Presse médicale·Jean-Marc TrocelloFrance Woimant
Jan 14, 2012·Gastroenterology·Dominik HusterSvetlana Lutsenko
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Oct 17, 2016·Biometals : an International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine·Ranjeet KumarPernilla Wittung-Stafshede
Jun 28, 2017·Metallomics : Integrated Biometal Science·Kumaravel Ponnandai ShanmugavelPernilla Wittung-Stafshede
Oct 25, 2017·Biometals : an International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine·Candan AriözPernilla Wittung-Stafshede
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Jul 20, 2019·Metallomics : Integrated Biometal Science·Kumaravel Ponnandai Shanmugavel, Pernilla Wittung-Stafshede
Dec 20, 2008·The Journal of Biological Chemistry·Maria Carmela Bonaccorsi di PattiGiovanni Musci

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