6IV2

Crystal structure of a bacterial Bestrophin homolog from Klebsiella pneumoniae with a mutation Y211A

Summary for 6IV2

• Entry DOI: 10.2210/pdb6iv2/pdb
• Related: 4wd8
• Descriptor: Bestrophin homolog, ZINC ION (3 entities in total)
• Functional Keywords: bestrophin-1, homolog, mutation, klebsiella pneumoniae, membrane protein
• Biological source: Klebsiella pneumoniae IS53
• Total number of polymer chains: 5
• Total formula weight: 169045.26

Authors

Kittredge, A.,Chen, S.,Yang, T. (deposition date: 2018-12-02, release date: 2019-11-13, Last modification date: 2024-05-29)

Primary citation

Ji, C.,Kittredge, A.,Hopiavuori, A.,Ward, N.,Chen, S.,Fukuda, Y.,Zhang, Y.,Yang, T.
Dual Ca2+-dependent gates in human Bestrophin1 underlie disease-causing mechanisms of gain-of-function mutations.
Commun Biol, 2:240-240, 2019

PubMed Abstract: Mutations of human , encoding a Ca-activated Cl channel (hBest1), cause macular degenerative disorders. Best1 homolog structures reveal an evolutionarily conserved channel architecture highlighted by two landmark restrictions (named the "neck" and "aperture", respectively) in the ion conducting pathway, suggesting a unique dual-switch gating mechanism, which, however, has not been characterized well. Using patch clamp and crystallography, we demonstrate that both the neck and aperture in hBest1 are Ca-dependent gates essential for preventing channel leakage resulting from Ca-independent, spontaneous gate opening. Importantly, three patient-derived mutations (D203A, I205T and Y236C) lead to Ca-independent leakage and elevated Ca-dependent anion currents due to enhanced opening of the gates. Moreover, we identify a network of residues critically involved in gate operation. Together, our results suggest an indispensable role of the neck and aperture of hBest1 for channel gating, and uncover disease-causing mechanisms of hBest1 gain-of-function mutations.

PubMed: 31263784
DOI: 10.1038/s42003-019-0433-3

Experimental method

X-RAY DIFFRACTION (2.62 Å)