Mózner, O.; Zámbó, B.; Bartos, Z.; Gergely, A.; Szabó, K.S.; Jezsó, B.; Telbisz, Á.; Várady, G.; Homolya, L.; Hegedűs, T.; Sarkadi, B. Expression, Function and Trafficking of the Human ABCG2 Multidrug Transporter Containing Mutations in an Unstructured Cytoplasmic Loop. Membranes2023, 13, 822.
Mózner, O.; Zámbó, B.; Bartos, Z.; Gergely, A.; Szabó, K.S.; Jezsó, B.; Telbisz, Á.; Várady, G.; Homolya, L.; Hegedűs, T.; Sarkadi, B. Expression, Function and Trafficking of the Human ABCG2 Multidrug Transporter Containing Mutations in an Unstructured Cytoplasmic Loop. Membranes 2023, 13, 822.
Mózner, O.; Zámbó, B.; Bartos, Z.; Gergely, A.; Szabó, K.S.; Jezsó, B.; Telbisz, Á.; Várady, G.; Homolya, L.; Hegedűs, T.; Sarkadi, B. Expression, Function and Trafficking of the Human ABCG2 Multidrug Transporter Containing Mutations in an Unstructured Cytoplasmic Loop. Membranes2023, 13, 822.
Mózner, O.; Zámbó, B.; Bartos, Z.; Gergely, A.; Szabó, K.S.; Jezsó, B.; Telbisz, Á.; Várady, G.; Homolya, L.; Hegedűs, T.; Sarkadi, B. Expression, Function and Trafficking of the Human ABCG2 Multidrug Transporter Containing Mutations in an Unstructured Cytoplasmic Loop. Membranes 2023, 13, 822.
Abstract
The human ABCG2 multidrug transporter plays a crucial role in the absorption and excretion of xeno- and endobiotics, contributes to cancer drug resistance and the development of gout. In this work we have analyzed the effects of selected variants, residing in a structurally unresolved cytoplasmic region (a.a. 354-367) of ABCG2, on the function and trafficking of this protein. A cluster of four lysines (K357-360) and the phosphorylation of a threonine (T362) residue in this region have been previously suggested to significantly affect the cellular fate of ABCG2. Here we report that the naturally occurring K360del variant in human cells increased ABCG2 plasma membrane expression and accelerated cellular trafficking. The variable alanine replacements of the neighboring lysines had no significant effect on transport function, and the apical localization of ABCG2 in polarized cells has not been altered by any of these mutations. Moreover, in contrast to previous reports, we found that the phosphorylation incompetent T362A, or the phosphorylation mimicking T362E variants in this loop, had no measurable effects on the function or expression of ABCG2. Molecular dynamics simulations indicated an increased mobility of the mutant variants with no major effects on the core structure of the protein. These results may help to decipher the potential role of this unstructured region within this transporter.
Biology and Life Sciences, Biochemistry and Molecular Biology
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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