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-Structure paper
Title | Structures and gating mechanisms of human bestrophin anion channels. |
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Journal, issue, pages | Nat Commun, Vol. 13, Issue 1, Page 3836, Year 2022 |
Publish date | Jul 4, 2022 |
Authors | Aaron P Owji / Jiali Wang / Alec Kittredge / Zada Clark / Yu Zhang / Wayne A Hendrickson / Tingting Yang / |
PubMed Abstract | Bestrophin-1 (Best1) and bestrophin-2 (Best2) are two members of the bestrophin family of calcium (Ca)-activated chloride (Cl) channels with critical involvement in ocular physiology and direct ...Bestrophin-1 (Best1) and bestrophin-2 (Best2) are two members of the bestrophin family of calcium (Ca)-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. Ca-bound Best1 structures illustrate partially open conformations at the two Ca-dependent gates of the channels, in contrast to the fully open conformations observed in Ca-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. |
External links | Nat Commun / PubMed:35789156 / PubMed Central |
Methods | EM (single particle) |
Resolution | 1.78 - 3.11 Å |
Structure data | EMDB-27127, PDB-8d1e: EMDB-27128, PDB-8d1f: EMDB-27129, PDB-8d1g: EMDB-27130, PDB-8d1h: EMDB-27131, PDB-8d1i: EMDB-27132, PDB-8d1j: EMDB-27133, PDB-8d1k: EMDB-27134, PDB-8d1l: EMDB-27135, PDB-8d1m: EMDB-27136, PDB-8d1n: EMDB-27137, PDB-8d1o: |
Chemicals | ChemComp-CA: ChemComp-MC3: ChemComp-DU0: ChemComp-CL: ChemComp-HOH: |
Source |
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Keywords | TRANSPORT PROTEIN / Ion channel / chloride channel / anion channel / pentamer |