7N16

Structure of TAX-4_R421W apo closed state

7N16 の概要

• エントリーDOI: 10.2210/pdb7n16/pdb
• 関連するPDBエントリー: 7N15
• EMDBエントリー: 24113 24114
• 分子名称: Cyclic nucleotide-gated cation channel, 1-PALMITOYL-2-LINOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE, SODIUM ION (3 entities in total)
• 機能のキーワード: ion channel, blindness-associated mutation, achromatopsia, phototransduction, transport protein
• 由来する生物種: Caenorhabditis elegans
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 349491.61

構造登録者

Zheng, X.,Li, H.,Hu, Z.,Su, D.,Yang, J. (登録日: 2021-05-27, 公開日: 2022-03-16)

主引用文献

Zheng, X.,Li, H.,Hu, Z.,Su, D.,Yang, J.
Structural and functional characterization of an achromatopsia-associated mutation in a phototransduction channel.
Commun Biol, 5:190-190, 2022

PubMed Abstract: Numerous missense mutations in cyclic nucleotide-gated (CNG) channels cause achromatopsia and retinitis pigmentosa, but the underlying pathogenic mechanisms are often unclear. We investigated the structural basis and molecular/cellular effects of R410W, an achromatopsia-associated, presumed loss-of-function mutation in human CNGA3. Cryo-EM structures of the Caenorhabditis elegans TAX-4 CNG channel carrying the analogous mutation, R421W, show that most apo channels are open. R421, located in the gating ring, interacts with the S4 segment in the closed state. R421W disrupts this interaction, destabilizes the closed state, and stabilizes the open state. CNGA3_R410W/CNGB3 and TAX4_R421W channels are spontaneously active without cGMP and induce cell death, suggesting cone degeneration triggered by spontaneous CNG channel activity as a possible cause of achromatopsia. Our study sheds new light on CNG channel allosteric gating, provides an impetus for a reevaluation of reported loss-of-function CNG channel missense disease mutations, and has implications for mutation-specific treatment of retinopathy.

PubMed: 35233102
DOI: 10.1038/s42003-022-03120-6

実験手法

ELECTRON MICROSCOPY (3.2 Å)