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Interactomes of WT and H1069Q variants of ATP7B

ABSTRACT: The H1069Q substitution in the liver-specific copper transporter ATP7B represents the major cause of Wilson disease. The mutated ATP7B undergoes rapid degradation in the endoplasmic reticulum (ER) and fails to reach copper excretion compartments thus causing severe copper toxicosis in patients. Modulating the ATP7B-H1069Q interactome was proposed as a rescue strategy but specific binding partners that might be targeted for mutant correction remain elusive. Here we try to identify a mutant-specific interactor for the pharmacological rescue of ATP7B-H1069Q.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hepatocyte, Cell Culture

DISEASE(S): Wilson Disease

SUBMITTER: Roman Polishchuk

LAB HEAD: Roman Polishchuk

PROVIDER: PXD016816 | Pride | 2020-12-11

REPOSITORIES: Pride

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Pharmacoproteomics pinpoints HSP70 interaction for correction of the most frequent Wilson disease-causing mutant of ATP7B.

Concilli Mafalda M Petruzzelli Raffaella R Parisi Silvia S Catalano Federico F Sirci Francesco F Napolitano Francesco F Renda Mario M Galietta Luis J V LJV Di Bernardo Diego D Polishchuk Roman S RS

Proceedings of the National Academy of Sciences of the United States of America 20201207 51

Pathogenic mutations in the copper transporter <i>ATP7B</i> have been hypothesized to affect its protein interaction landscape contributing to loss of function and, thereby, to hepatic copper toxicosis in Wilson disease. Although targeting mutant interactomes was proposed as a therapeutic strategy, druggable interactors for rescue of ATP7B mutants remain elusive. Using proteomics, we found that the frequent H1069Q substitution promotes ATP7B interaction with HSP70, thus accelerating endoplasmic ...[more]

PMID: 33288711

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