Structures and gating mechanisms of human bestrophin anion channels

Nat Commun. 2022 Jul 4;13(1):3836. doi: 10.1038/s41467-022-31437-7.

Abstract

Bestrophin-1 (Best1) and bestrophin-2 (Best2) are two members of the bestrophin family of calcium (Ca2+)-activated chloride (Cl-) channels with critical involvement in ocular physiology and direct pathological relevance. Here, we report cryo-EM structures of wild-type human Best1 and Best2 in various states at up to 1.8 Å resolution. Ca2+-bound Best1 structures illustrate partially open conformations at the two Ca2+-dependent gates of the channels, in contrast to the fully open conformations observed in Ca2+-bound Best2, which is in accord with the significantly smaller currents conducted by Best1 in electrophysiological recordings. Comparison of the closed and open states reveals a C-terminal auto-inhibitory segment (AS), which constricts the channel concentrically by wrapping around the channel periphery in an inter-protomer manner and must be released to allow channel opening. Our results demonstrate that removing the AS from Best1 and Best2 results in truncation mutants with similar activities, while swapping the AS between Best1 and Best2 results in chimeric mutants with swapped activities, underlying a key role of the AS in determining paralog specificity among bestrophins.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bestrophins / genetics
  • Calcium / metabolism
  • Chloride Channels* / genetics
  • Chlorides / metabolism
  • Eye Proteins* / genetics
  • Eye Proteins* / metabolism
  • Humans

Substances

  • BEST1 protein, human
  • Bestrophins
  • Chloride Channels
  • Chlorides
  • Eye Proteins
  • Calcium