Abstract
The H1069Q substitution is the most frequent mutation of the Cu transporter ATP7B that causes Wilson disease in the Caucasian population. ATP7B localizes to the Golgi complex in hepatocytes, but, in the presence of excessive Cu, it relocates to the endo-lysosomal compartment to excrete Cu via bile canaliculi. In contrast, ATP7B-H1069Q is strongly retained in the ER, does not reach the Golgi complex and fails to move to the endo-lysosomal compartment in the presence of excessive Cu, thus causing toxic Cu accumulation. We have previously shown that, in transfected cells, the small heat-shock protein αB-crystallin is able to correct the mislocalization of ATP7B-H1069Q and its trafficking in the presence of Cu overload. Here, we first show that the α-crystallin domain of αB-crystallin mimics the effect of the full-length protein, whereas the N- and C-terminal domains have no such effect. Next, and most importantly, we demonstrate that a twenty-residue peptide derived from the α-crystallin domain of αB-crystallin fully rescues Golgi localization and the trafficking response of ATP7B-H1069Q in the presence of Cu overload. In addition, we show that this peptide interacts with the mutant transporter in the live cell. These results open the way to attempt developing a pharmacologically active peptide to specifically contrast the Wilson disease form caused by the ATP7B-H1069Q mutant.
Highlights
Wilson disease (WD) is a relatively frequent inherited liver disorder characterized by a slow onset of insurgence [1,2]
We have previously shown that, in transfected cells, the small heat-shock protein αB-crystallin is able to correct the mislocalization of ATP7B-H1069Q and its trafficking in the presence of Cu overload
ATP7B is localized in the trans-Golgi network (TGN) of the hepatocytes and pumps Cu from the cytosol into the lumen where Cu ions are captured by protein acceptors such as the serum protein Ceruloplasmin [12,13]
Summary
Wilson disease (WD) is a relatively frequent inherited liver disorder (about 1:7000 birth cases) characterized by a slow onset of insurgence [1,2]. The H1069Q substitution resides in and influences the nucleotide binding domain of the transporter, quite a significant residual level of transport activity is still borne by the mutant protein [9,15] This residual transport activity is useless (and probably deleterious), while it would be most likely sufficient to prevent/largely ameliorate the disease if the protein would be first correctly located in the TGN and able to reach the endo-lysosomal compartment in the presence of Cu overload [16]. We have previously shown that the small heath shock protein αB-crystallin (HspB5 or CRYAB) is able to prevent aggregation of ATP7B-H1069Q and efficiently restore both Golgi localization and trafficking to the endo-lysosomal compartment of the mutant transporter [10]. We demonstrate its interaction with the mutant transporter in the live cell
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