Processing mutations disrupt interactions between the nucleotide binding and transmembrane domains of P-glycoprotein and the cystic fibrosis transmembrane conductance regulator (CFTR).

The Journal of Biological Chemistry
Tip W LooDavid M Clarke

Abstract

P-glycoprotein (P-gp, ABCB1) is an ATP-dependent drug pump. Each of its two homologous halves contains a transmembrane domain (TMD) that has six transmembrane (TM) segments and a nucleotide-binding domain (NBD). Determining how the two halves interact may provide insight into the folding of P-gp as the drug-binding pocket and nucleotide-binding sites are predicted to be at the interface between the two halves. Here, we present evidence for NBD1-TMD2 and NBD2-TMD1 interactions. We also show that TMD-NBD interactions in immature and mature P-gp can be affected by the presence of a processing mutation. We found that the NBD-TMD mutants L443C(NBD1)/S909C(TMD2) and A266C(TMD1)/F1086C(NBD2) could be cross-linked at 0 degrees C with oxidant (copper phenanthroline). Cross-linking was inhibited by vanadate-trapping of nucleotide. The presence of a processing mutation (G268V/L443C(NBD1)/S909C(TMD2); L1260A/A266C(TMD1)/F1086C(NBD2)) resulted in the synthesis of the immature (150 kDa) protein as the major product and the mutants could not be cross-linked with copper phenanthroline. Expression of the processing mutants in the presence of a pharmacological chaperone (cyclosporin A), however, resulted in the expression of mature (170 kDa) pro...Continue Reading

References

Nov 1, 1987·Proceedings of the National Academy of Sciences of the United States of America·F ThiebautM C Willingham
May 1, 1968·Biochimica Et Biophysica Acta·K Kobashi
Sep 15, 1995·The Journal of Biological Chemistry·T W Loo, D M Clarke
Aug 18, 1995·The Journal of Biological Chemistry·I L UrbatschA E Senior
Jan 13, 1995·The Journal of Biological Chemistry·T W Loo, D M Clarke
Jan 10, 1997·The Journal of Biological Chemistry·T W Loo, D M Clarke
Jun 1, 1997·Seminars in Cancer Biology·A E Senior, D C Gadsby
Aug 26, 1998·Methods in Enzymology·T W Loo, D M Clarke
May 20, 1999·Annual Review of Pharmacology and Toxicology·S V AmbudkarM M Gottesman
Oct 3, 1999·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·T W Loo, D M Clarke
Mar 14, 2002·Proceedings of the National Academy of Sciences of the United States of America·Tip W Loo, David M Clarke
Aug 30, 2005·The Journal of Clinical Investigation·Nicoletta PedemonteA S Verkman
Oct 26, 2005·Molecular Cell·Bertrand KleizenIneke Braakman
Feb 4, 2006·The Journal of Membrane Biology·T W Loo, D M Clarke
Sep 1, 2006·Nature·Roger J P Dawson, Kaspar P Locher
Jul 14, 2007·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Joseph K ZolnerciksKenneth J Linton
Feb 29, 2008·Proceedings of the National Academy of Sciences of the United States of America·Adrian W R SerohijosJohn R Riordan
Mar 11, 2008·Archives of Biochemistry and Biophysics·Tip W Loo, David M Clarke
Mar 26, 2008·The Biochemical Journal·Tip W LooDavid M Clarke

❮ Previous
Next ❯

Citations

Apr 25, 2013·Journal of Computer-aided Molecular Design·Rameshwar PrajapatiAbhay T Sangamwar
Mar 20, 2009·Proceedings of the National Academy of Sciences of the United States of America·Giani OanceaRobert Tampé
Jan 3, 2012·Proceedings of the National Academy of Sciences of the United States of America·Qian DongMichael J Welsh
Oct 30, 2012·Toxicological Sciences : an Official Journal of the Society of Toxicology·Elnaz GozalpourJan B Koenderink
Jan 23, 2009·BMC Structural Biology·Jean-Paul BeckerMartine Prévost
Sep 8, 2009·Theoretical Biology & Medical Modelling·Aina W RavnaGeorg Sager
Sep 14, 2011·PloS One·Pedro Eduardo FerreiraJosé Pedro Gil
Jun 28, 2014·Biomolecules·Xiaodong Robert Wang, Chenglong Li
Aug 27, 2009·Cellular and Molecular Life Sciences : CMLS·Jean-Paul MornonIsabelle Callebaut
Dec 6, 2011·Trends in Molecular Medicine·Gergely L Lukacs, A S Verkman
Dec 15, 2011·Biochemical and Biophysical Research Communications·Rajendra PrasadKhyati Kapoor
Apr 17, 2010·Biochemical and Biophysical Research Communications·Tip W LooDavid M Clarke
Mar 6, 2016·Biochemical and Biophysical Research Communications·Tip W Loo, David M Clarke
Apr 28, 2011·Biochemistry·Tip W LooDavid M Clarke
Oct 25, 2013·Protein Science : a Publication of the Protein Society·Jingzhi LiStephen G Aller
Jul 10, 2013·Biochemical Pharmacology·Tip W LooDavid M Clarke
Dec 18, 2013·Molecular Membrane Biology·Paul Linsdell
May 30, 2009·Chemistry & Biology·Patrick Kim ChiawChristine E Bear
Oct 5, 2016·Cellular and Molecular Life Sciences : CMLS·Carlos M Farinha, Sara Canato
Jun 9, 2009·American Journal of Respiratory Cell and Molecular Biology·Asta JurkuvenaiteJames F Collawn
May 20, 2015·The Journal of Biological Chemistry·Tip W Loo, David M Clarke

❮ Previous
Next ❯

Related Concepts

Related Feeds

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.