Evidence for a credit-card-swipe mechanism in the human PC floppase ABCB4

Structure. 2021 Oct 7;29(10):1144-1155.e5. doi: 10.1016/j.str.2021.05.013. Epub 2021 Jun 8.

Abstract

ABCB4 is described as an ATP-binding cassette (ABC) transporter that primarily transports lipids of the phosphatidylcholine (PC) family but is also capable of translocating a subset of typical multidrug-resistance-associated drugs. The high degree of amino acid identity of 76% for ABCB4 and ABCB1, which is a prototype multidrug-resistance-mediating protein, results in ABCB4's second subset of substrates, which overlap with ABCB1's substrates. This often leads to incomplete annotations of ABCB4, in which it was described as exclusively PC-lipid specific. When the hydrophilic amino acids from ABCB4 are changed to the analogous but hydrophobic ones from ABCB1, the stimulation of ATPase activity by 1,2-dioleoyl-sn-glycero-3-phosphocholine, as a prime example of PC lipids, is strongly diminished, whereas the modulation capability of ABCB1 substrates remains unchanged. This indicates two distinct and autonomous substrate binding sites in ABCB4.

Keywords: ABC transporter; ABCB1; ABCB4; ATPases; MD simulation; MDR3; PC lipids; credit card swipe; drugs; two-site access model.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / chemistry*
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • Binding Sites
  • Humans
  • Molecular Dynamics Simulation
  • Phosphatidylcholines / metabolism
  • Protein Binding

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • Phosphatidylcholines
  • multidrug resistance protein 3