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-Structure paper
タイトル | Structural and functional characterization of an achromatopsia-associated mutation in a phototransduction channel. |
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ジャーナル・号・ページ | Commun Biol, Vol. 5, Issue 1, Page 190, Year 2022 |
掲載日 | 2022年3月1日 |
![]() | Xiangdong Zheng / Huan Li / Zhengshan Hu / Deyuan Su / Jian Yang / ![]() |
PubMed 要旨 | 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 ...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. |
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手法 | EM (単粒子) |
解像度 | 2.9 - 3.2 Å |
構造データ | EMDB-24113, PDB-7n15: EMDB-24114, PDB-7n16: EMDB-24115, PDB-7n17: |
化合物 | ![]() ChemComp-PCG: ![]() ChemComp-CPL: ![]() ChemComp-PX2: ![]() ChemComp-NA: |
由来 |
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![]() | TRANSPORT PROTEIN / ion channel / blindness-associated mutation / achromatopsia / phototransduction |