ABCMdb

ABCG2 p.Lys473Trp

Predicted by SNAP2:	A: D (75%), C: D (71%), D: D (85%), E: D (85%), F: D (85%), G: D (75%), H: D (71%), I: D (80%), L: D (75%), M: D (66%), N: D (66%), P: D (91%), Q: D (66%), R: D (66%), S: D (71%), T: D (71%), V: D (80%), W: D (85%), Y: D (80%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

[switch to compact view]
Comments [show]

None has been submitted yet.

Publications
[hide] Gout-causing Q141K mutation in ABCG2 leads to inst... Proc Natl Acad Sci U S A. 2013 Mar 26;110(13):5223-8. doi: 10.1073/pnas.1214530110. Epub 2013 Mar 14. Woodward OM, Tukaye DN, Cui J, Greenwell P, Constantoulakis LM, Parker BS, Rao A, Kottgen M, Maloney PC, Guggino WB
Gout-causing Q141K mutation in ABCG2 leads to instability of the nucleotide-binding domain and can be corrected with small molecules.
Proc Natl Acad Sci U S A. 2013 Mar 26;110(13):5223-8. doi: 10.1073/pnas.1214530110. Epub 2013 Mar 14., [PMID:23493553]

Abstract [show]
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 (DeltaF508) in the cystic fibrosis transmembrane conductance regulator (CFTR). We found, much like in DeltaF508 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.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
89 Significantly, introduction of the K473W substitution on the Q141K background did not rescue total, mature, or dimer levels (all were actually significantly less) (Fig. 4 A-C and Fig. S5E). Login to comment
90 The failure of the K473W mutation to rescue Q141K expression supports the hypothesis that the Q141K mutation does not interfere with interdomain interactions or dimerization of the ABCG2 protein. Login to comment
134 Western blots of total (A) and dimer (B) expression of Q141K ABCG2 with secondary mutations at K473 demonstrating that K473W cannot rescue Q141K expression. Login to comment