Unknown

Dataset Information

0

Gout-causing Q141K mutation in ABCG2 leads to instability of the nucleotide-binding domain and can be corrected with small molecules.


ABSTRACT: The multidrug ATP-binding cassette, subfamily G, 2 (ABCG2) transporter was recently identified as an important human urate transporter, and a common mutation, a Gln to Lys substitution at position 141 (Q141K), was shown to cause hyperuricemia and gout. The nature of the Q141K defect, however, remains undefined. Here we explore the Q141K ABCG2 mutation using a comparative approach, contrasting it with another disease-causing mutation in an ABC transporter, the deletion of Phe-508 (?F508) in the cystic fibrosis transmembrane conductance regulator (CFTR). We found, much like in ?F508 CFTR, that the Q141K mutation leads to instability in the nucleotide-binding domain (NBD), a defect that translates to significantly decreased protein expression. However, unlike the CFTR mutant, the Q141K mutation does not interfere with the nucleotide-binding domain/intracellular loop interactions. This investigation has also led to the identification of critical residues involved in the protein-protein interactions necessary for the dimerization of ABCG2: Lys-473 (K473) and Phe-142 (F142). Finally, we have demonstrated the utility of using small molecules to correct the Q141K defect in expression and function as a possible therapeutic approach for hyperuricemia and gout.

SUBMITTER: Woodward OM 

PROVIDER: S-EPMC3612674 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

altmetric image

Publications

Gout-causing Q141K mutation in ABCG2 leads to instability of the nucleotide-binding domain and can be corrected with small molecules.

Woodward Owen M OM   Tukaye Deepali N DN   Cui Jinming J   Greenwell Patrick P   Constantoulakis Leeza M LM   Parker Benjamin S BS   Rao Anjana A   Köttgen Michael M   Maloney Peter C PC   Guggino William B WB  

Proceedings of the National Academy of Sciences of the United States of America 20130314 13


The multidrug ATP-binding cassette, subfamily G, 2 (ABCG2) transporter was recently identified as an important human urate transporter, and a common mutation, a Gln to Lys substitution at position 141 (Q141K), was shown to cause hyperuricemia and gout. The nature of the Q141K defect, however, remains undefined. Here we explore the Q141K ABCG2 mutation using a comparative approach, contrasting it with another disease-causing mutation in an ABC transporter, the deletion of Phe-508 (ΔF508) in the c  ...[more]

Similar Datasets

| S-EPMC7265540 | biostudies-literature
| S-EPMC4637776 | biostudies-literature
| S-EPMC2700910 | biostudies-literature
| S-EPMC5424544 | biostudies-literature
| S-EPMC4023295 | biostudies-literature
| S-EPMC8638943 | biostudies-literature
| S-EPMC8242189 | biostudies-literature
| S-EPMC2628956 | biostudies-literature
| S-EPMC4621745 | biostudies-literature
| S-EPMC5706492 | biostudies-literature