Single nucleotide polymorphisms in the human ATP7B gene modify the properties of the ATP7B protein

Courtney J. McCann; Samuel Jayakanthan; Mariacristina Siotto; Nan Yang; Maria Osipova; Rosanna Squitti; Svetlana Lutsenko

doi:10.1039/C9MT00057G

Single nucleotide polymorphisms in the human ATP7B gene modify the properties of the ATP7B protein†

Courtney J. McCann,^a Samuel Jayakanthan,^a Mariacristina Siotto,^b Nan Yang,^a Maria Osipova,^a Rosanna Squitti^c and Svetlana Lutsenko*^a

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* Corresponding authors

^a Department of Physiology, Johns Hopkins University, Baltimore, MD, USA
E-mail: Lutsenko@jhmi.edu

^b Don Carlo Gnocchi ONLUS Foundation, Milan, Italy

^c IRCCS Istituto Centro San Giovanni di Dio-Fatebenefratelli, Italy

Abstract

Single nucleotide polymorphisms (SNPs) are the largest source of sequence variation in the human genome. However, their functional significance is not well understood. We show that SNPs in the Wilson disease gene, ATP7B, that produce amino-acid substitutions K832R and R952K, modulate ATP7B properties in vitro and influence serum copper (Cu) status in vivo. The presence of R832 is associated with a lower ATP7B abundance and a diminished trafficking in response to elevated Cu. The K832R substitution alters surface exposure of amino acid residues in the actuator domain and increases its conformational flexibility. All SNP-related ATP7B variants (R832/R952, R832/K952, K832/K952, and K832/R952) have Cu-transport activity. However, the activity of ATP7B-K832/K952 is lower compared to other variants. In humans, the presence of K952 is associated with a higher fraction of exchangeable Cu in serum. Thus, SNPs may modulate the properties of ATP7B and the organism Cu status.

Metallomics

Single nucleotide polymorphisms in the human ATP7B gene modify the properties of the ATP7B protein†

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