|
|
||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital Campus, London, UK
1Correspondence: MRC Clinical Sciences Centre, Imperial College, Hammersmith Hospital Campus, Du Cane Rd., London W12 0NN, UK. E-mail: kenneth.linton{at}csc.mrc.ac.uk
The recently reported structures of the bacterial multidrug exporter Sav1866 suggest a domain architecture in which both nucleotide-binding domains (NBDs) of this ATP binding cassette (ABC) transporter contact both transmembrane domains (TMDs). Such a domain arrangement is particularly unexpected because it is not found in the structures of three solute importers BtuCD, HI1470/1, and ModBC from the same protein family. There is also no precedent for such an arrangement from biochemical studies with any ABC transporter. Sav1866 is homologous with the clinically relevant human P-glycoprotein (ABCB1). If the structure proposed for Sav1866 is physiologically relevant, the long intracellular loops of P-glycoprotein TMD2 should contact NBD1. We have tested this by using cysteine mutagenesis and chemical cross-linking to verify proximal relationships of the introduced sulfhydryls across the proposed interdomain interface. We report the first biochemical evidence in support of the domain arrangement proposed for the multidrug resistance class of ABC transporters. With a domain arrangement distinctly different from the three solute importers it seems likely that the TMDs of ABC importers and exporters have evolved different mechanisms to couple to common conformational changes at conserved NBDs.—Zolnerciks, J. K., Wooding, C., Linton, K. J. Evidence for a Sav1866-like architecture for the human multidrug transporter P-glycoprotein.
Key Words: ATP binding cassette transporter drug efflux ABC protein MDR1 ABCB1
This article has been cited by other articles:
![]() |
A. A. Aleksandrov, L. Cui, and J. R. Riordan Relationship between nucleotide binding and ion channel gating in cystic fibrosis transmembrane conductance regulator J. Physiol., June 15, 2009; 587(12): 2875 - 2886. [Abstract] [Full Text] [PDF] |
||||
![]() |
G. Oancea, M. L. O'Mara, W. F. D. Bennett, D. P. Tieleman, R. Abele, and R. Tampe Structural arrangement of the transmission interface in the antigen ABC transport complex TAP PNAS, April 7, 2009; 106(14): 5551 - 5556. [Abstract] [Full Text] [PDF] |
||||
![]() |
P H Dixon, S W C van Mil, J Chambers, S Strautnieks, R J Thompson, F Lammert, R Kubitz, V Keitel, A Glantz, L-A Mattsson, et al. Contribution of variant alleles of ABCB11 to susceptibility to intrahepatic cholestasis of pregnancy Gut, April 1, 2009; 58(4): 537 - 544. [Abstract] [Full Text] [PDF] |
||||
![]() |
K. P Locher Structure and mechanism of ATP-binding cassette transporters Phil Trans R Soc B, January 27, 2009; 364(1514): 239 - 245. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. Dietrich, H. Schmuths, C. D. M. Lousa, J. M. Baldwin, S. A. Baldwin, A. Baker, F. L. Theodoulou, and M. J. Holdsworth Mutations in the Arabidopsis Peroxisomal ABC Transporter COMATOSE Allow Differentiation between Multiple Functions In Planta: Insights from an Allelic Series Mol. Biol. Cell, January 1, 2009; 20(1): 530 - 543. [Abstract] [Full Text] [PDF] |
||||
![]() |
Z. E. Sauna, S. S. Bohn, R. Rutledge, M. P. Dougherty, S. Cronin, L. May, D. Xia, S. V. Ambudkar, and J. Golin Mutations Define Cross-talk between the N-terminal Nucleotide-binding Domain and Transmembrane Helix-2 of the Yeast Multidrug Transporter Pdr5: POSSIBLE CONSERVATION OF A SIGNALING INTERFACE FOR COUPLING ATP HYDROLYSIS TO DRUG TRANSPORT J. Biol. Chem., December 12, 2008; 283(50): 35010 - 35022. [Abstract] [Full Text] [PDF] |
||||
![]() |
T. W. Loo, M. C. Bartlett, and D. M. Clarke Processing Mutations Disrupt Interactions between the Nucleotide Binding and Transmembrane Domains of P-glycoprotein and the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) J. Biol. Chem., October 17, 2008; 283(42): 28190 - 28197. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. Pagant, E. Y. Brovman, J. J. Halliday, and E. A. Miller Mapping of Interdomain Interfaces Required for the Functional Architecture of Yor1p, a Eukaryotic ATP-binding Cassette (ABC) Transporter J. Biol. Chem., September 26, 2008; 283(39): 26444 - 26451. [Abstract] [Full Text] [PDF] |
||||
![]() |
L. He, A. A. Aleksandrov, A. W. R. Serohijos, T. Hegedus, L. A. Aleksandrov, L. Cui, N. V. Dokholyan, and J. R. Riordan Multiple Membrane-Cytoplasmic Domain Contacts in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Mediate Regulation of Channel Gating J. Biol. Chem., September 26, 2008; 283(39): 26383 - 26390. [Abstract] [Full Text] [PDF] |
||||
![]() |
T. W. Loo, M. C. Bartlett, and D. M. Clarke Arginines in the First Transmembrane Segment Promote Maturation of a P-glycoprotein Processing Mutant by Hydrogen Bond Interactions with Tyrosines in Transmembrane Segment 11 J. Biol. Chem., September 5, 2008; 283(36): 24860 - 24870. [Abstract] [Full Text] [PDF] |
||||
![]() |
Y. Shi, X. Chen, Z. Wu, W. Shi, Y. Yang, N. Cui, C. Jiang, and R. W. Harrison cAMP-dependent Protein Kinase Phosphorylation Produces Interdomain Movement in SUR2B Leading to Activation of the Vascular KATP Channel J. Biol. Chem., March 21, 2008; 283(12): 7523 - 7530. [Abstract] [Full Text] [PDF] |
||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |