Relationship between conformation shift and disease related variation sites in ATP-binding cassette transporter proteins

Mika Sakamoto, Hirofumi Suzuki, Kei Yura*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Transport of small molecules across the cell membrane is a crucial biological mechanism for the maintenance of the cell activity. ABC transporter family is a huge group in the transporter membrane proteins and actively transports the substrates using the energy derived from ATP hydrolysis. In humans, there are 48 distinct genes for ABC transporters. A variation of a single amino acid in the amino acid sequence of ABC transporter has been known to be linked with certain disease. The mechanism of the onset of the disease by the variation is, however, still unclear. Recent progress in the method to measure the structures of huge membrane proteins has enabled determination of the 3D structures of ABC transporters and the accumulation of coordinate data of ABC transporter has enabled us to obtain clues for the onset of the disease caused by a single variation of amino acid residue. We compared the structures of ABC transporter in apo and ATP-binding forms and found a possible conformation shift around pivot-like residues in the transmembrane domains. When this conformation change in ABC transporter and the location of pathogenic variation were compared, we found a reasonable match between the two, explaining the onset of the disease by the variation. They likely cause impairment of the pivot-like movement, weakening of ATP binding and weakening of membrane surface interactions. These findings will give a new interpretation of the variations on ABC transporter genes and pave a way to analyse the effect of variation on protein structure and function.

Original languageEnglish
Pages (from-to)68-79
Number of pages12
JournalBiophysics and physicobiology
Volume16
DOIs
Publication statusPublished - 2019

Keywords

  • coupling helix
  • differential map
  • pathogenic variation
  • pivot-like residue
  • protein 3D structure

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Physiology
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)

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