TY - JOUR
T1 - Single nucleotide polymorphisms in the human
T2 - ATP7B gene modify the properties of the ATP7B protein
AU - McCann, Courtney J.
AU - Jayakanthan, Samuel
AU - Siotto, Mariacristina
AU - Yang, Nan
AU - Osipova, Maria
AU - Squitti, Rosanna
AU - Lutsenko, Svetlana
N1 - Funding Information:
This work was supported by the National Research Council [Aging Program 2012-2014, 'A low-copper diet as a preventive strategy for cognitive disability in Aging']; Italian Ministry of Health [5XMille project 'Un metodo sensibile, diretto e preciso per misurare il rame Non-legato alla Ceruloplasmina nel siero per applicazione in ambiente clinico' 09/02/2013 to 08/31/2015]; Italian Ministry of Health ['Tolerability and efficacy of Zinc therapy in Mild Cognitive Impairment for treatment and prevention of Alzheimer's disease: a prospective, randomized, double blind, parallel, placebo controlled Phase II clinical trial' (Project Code: CO-2013-02358488)]; Canox4drug SpA [2013-2016 'Non-Ceruloplasmin copper in Alzheimer's disease' (Prot. 30/2013)], Italian Ministry of Health, Ricerca Corrente. This work was also funded in part by the National Institutes of Health grant R01 DK071865 (2SL).
Publisher Copyright:
© The Royal Society of Chemistry.
PY - 2019/6
Y1 - 2019/6
N2 - 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.
AB - 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.
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U2 - 10.1039/c9mt00057g
DO - 10.1039/c9mt00057g
M3 - Article
C2 - 31070637
AN - SCOPUS:85067542731
SN - 1756-5901
VL - 11
SP - 1128
EP - 1139
JO - Metallomics
JF - Metallomics
IS - 6
ER -