The linker region of breast cancer resistance protein ABCG2 is critical for coupling of ATP-dependent drug transport

S. Macalou, R. W. Robey, G. Jabor Gozzi, S. Shukla, I. Grosjean, T. Hegedűs, S. V. Ambudkar, S. E. Bates, A. Di Pietro

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The ATP-binding cassette (ABC) transporters of class G display a different domain organisation than P-glycoprotein/ABCB1 and bacterial homologues with a nucleotide-binding domain preceding the transmembrane domain. The linker region connecting these domains is unique and its function and structure cannot be predicted. Sequence analysis revealed that the human ABCG2 linker contains a LSGGE sequence, homologous to the canonical C-motif/ABC signature present in all ABC nucleotide-binding domains. Predictions of disorder and of secondary structures indicated that this C2-sequence was highly mobile and located between an α-helix and a loop similarly to the C-motif. Point mutations of the two first residues of the C2-sequence fully abolished the transport-coupled ATPase activity, and led to the complete loss of cell resistance to mitoxantrone. The interaction with potent, selective and non-competitive, ABCG2 inhibitors was also significantly altered upon mutation. These results suggest an important mechanistic role for the C2-sequence of the ABCG2 linker region in ATP binding and/or hydrolysis coupled to drug efflux.

Original languageEnglish
Pages (from-to)1-11
Number of pages11
JournalCellular and Molecular Life Sciences
DOIs
Publication statusAccepted/In press - Dec 26 2015

Fingerprint

Adenosine Triphosphate
Breast Neoplasms
Nucleotides
Pharmaceutical Preparations
Mitoxantrone
ATP-Binding Cassette Transporters
P-Glycoprotein
Sequence Homology
Point Mutation
Sequence Analysis
Adenosine Triphosphatases
Hydrolysis
Mutation
ATP Binding Cassette Transporter, Sub-Family G, Member 2

Keywords

  • ABC transporter
  • ATP hydrolysis
  • Breast cancer resistance protein/ABCG2
  • C motif/ABC signature
  • Drug efflux coupling
  • Specific sequence

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Molecular Medicine
  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

The linker region of breast cancer resistance protein ABCG2 is critical for coupling of ATP-dependent drug transport. / Macalou, S.; Robey, R. W.; Jabor Gozzi, G.; Shukla, S.; Grosjean, I.; Hegedűs, T.; Ambudkar, S. V.; Bates, S. E.; Di Pietro, A.

In: Cellular and Molecular Life Sciences, 26.12.2015, p. 1-11.

Research output: Contribution to journalArticle

Macalou, S. ; Robey, R. W. ; Jabor Gozzi, G. ; Shukla, S. ; Grosjean, I. ; Hegedűs, T. ; Ambudkar, S. V. ; Bates, S. E. ; Di Pietro, A. / The linker region of breast cancer resistance protein ABCG2 is critical for coupling of ATP-dependent drug transport. In: Cellular and Molecular Life Sciences. 2015 ; pp. 1-11.
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