title: 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 (ΔF508) in the cystic fibrosis transmembrane conductance regulator (CFTR). We found, much like in ΔF508 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.
authors.affiliation: Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. owenw@jhmi.edu
authors.forename: Owen M
authors.initials: OM
authors.lastname: Woodward
authors.forename: Deepali N
authors.initials: DN
authors.lastname: Tukaye
authors.forename: Jinming
authors.initials: J
authors.lastname: Cui
authors.forename: Patrick
authors.initials: P
authors.lastname: Greenwell
authors.forename: Leeza M
authors.initials: LM
authors.lastname: Constantoulakis
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Parker
authors.forename: Anjana
authors.initials: A
authors.lastname: Rao
authors.forename: Michael
authors.initials: M
authors.lastname: Köttgen
authors.forename: Peter C
authors.initials: PC
authors.lastname: Maloney
authors.forename: William B
authors.initials: WB
authors.lastname: Guggino
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D019943:Amino Acid Substitution; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism; D006073:Gout / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D033461:Hyperuricemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D014982:Xenopus laevis
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C505032:CFTR protein, human; D009363:Neoplasm Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator