The molecular principles underlying diverse functions of the SLC26 family of proteins

Satoe Takahashi, Kazuaki Homma*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Mammalian SLC26 proteins are membrane-based anion transporters that belong to the large SLC26/SulP family, and many of their variants are associated with hereditary diseases. Recent structural studies revealed a strikingly similar homodimeric molecular architecture for several SLC26 members, implying a shared molecular principle. Now a new question emerges as to how these structurally similar proteins execute diverse physiological functions. In this study, we sought to identify the common versus distinct molecular mechanism among the SLC26 proteins using both naturally occurring and artificial missense changes introduced to SLC26A4, SLC26A5, and SLC26A9. We found: (i) the basic residue at the anion binding site is essential for both anion antiport of SLC26A4 and motor functions of SLC26A5, and its conversion to a nonpolar residue is crucial but not sufficient for the fast uncoupled anion transport in SLC26A9; (ii) the conserved polar residues in the N- and C-terminal cytosolic domains are likely involved in dynamic hydrogen-bonding networks and are essential for anion antiport of SLC26A4 but not for motor (SLC26A5) and uncoupled anion transport (SLC26A9) functions; (iii) the hydrophobic interaction between each protomer's last transmembrane helices, TM14, is not of functional significance in SLC26A9 but crucial for the functions of SLC26A4 and SLC26A5, likely contributing to optimally orient the axis of the relative movements of the core domain with respect to the gate domains within the cell membrane. These findings advance our understanding of the molecular mechanisms underlying the diverse physiological roles of the SLC26 family of proteins.

Original languageEnglish (US)
Article number107261
JournalJournal of Biological Chemistry
Issue number5
StatePublished - May 2024


  • SLC26A4
  • SLC26A5
  • SLC26A9
  • chloride transport
  • exchanger
  • molecular motor
  • patch clamp
  • pendrin
  • prestin
  • structure-function

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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