An αB-Crystallin Peptide Rescues Compartmentalization and Trafficking Response to Cu Overload of ATP7B-H1069Q, the Most Frequent Cause of Wilson Disease in the Caucasian Population

International Journal of Molecular Sciences

Andrea Scaloni¹  MariaGabriella Caporaso¹  Michela Ciano²  MariaCamilla Ciardulli²  Massimo D’Agostino²  Simona Allocca²  Stefano Bonatti²  Daniela Sarnataro³  Chiara D’Ambrosio³ 

[1] Mass Spectrometry Laboratory, ISPAAM, National Research Council, Via Argine 1085, 80147 Naples, Italy;Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, via S. Pansini 5, 80131 Naples, Italy;;Proteomics &

关键词: ATP7B;    Wilson disease;    αB-crystallin;    pharmacological peptide;   

DOI  :  10.3390/ijms19071892

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown