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光敏感磷酸化调节视网膜 IMPDH1 活性和丝组装。

Light-sensitive phosphorylation regulates retinal IMPDH1 activity and filament assembly.

机构信息

Department of Biochemistry, University of Washington, Seattle, WA, USA.

Metabolic Engineering Group, Departamento de Microbiología y Genética, Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain.

出版信息

J Cell Biol. 2024 Apr 1;223(4). doi: 10.1083/jcb.202310139. Epub 2024 Feb 7.

DOI:10.1083/jcb.202310139
PMID:38323936
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10849882/
Abstract

Inosine monophosphate dehydrogenase (IMPDH) is the rate-limiting enzyme in guanosine triphosphate (GTP) synthesis and assembles into filaments in cells, which desensitizes the enzyme to feedback inhibition and boosts nucleotide production. The vertebrate retina expresses two splice variants IMPDH1(546) and IMPDH1(595). In bovine retinas, residue S477 is preferentially phosphorylated in the dark, but the effects on IMPDH1 activity and regulation are unclear. Here, we generated phosphomimetic mutants to investigate structural and functional consequences of S477 phosphorylation. The S477D mutation resensitized both variants to GTP inhibition but only blocked assembly of IMPDH1(595) filaments. Cryo-EM structures of both variants showed that S477D specifically blocks assembly of a high-activity assembly interface, still allowing assembly of low-activity IMPDH1(546) filaments. Finally, we discovered that S477D exerts a dominant-negative effect in cells, preventing endogenous IMPDH filament assembly. By modulating the structure and higher-order assembly of IMPDH, S477 phosphorylation acts as a mechanism for downregulating retinal GTP synthesis in the dark when nucleotide turnover is decreased.

摘要

肌苷单磷酸脱氢酶（IMPDH）是三磷酸鸟苷（GTP）合成的限速酶，在细胞中组装成纤维，使酶对反馈抑制脱敏并提高核苷酸产量。脊椎动物视网膜表达两种剪接变体 IMPDH1（546）和 IMPDH1（595）。在牛视网膜中，残基 S477 在黑暗中优先磷酸化，但对 IMPDH1 活性和调节的影响尚不清楚。在这里，我们生成了磷酸模拟突变体来研究 S477 磷酸化对结构和功能的影响。S477D 突变使两种变体对 GTP 抑制重新敏感，但仅阻止 IMPDH1（595）纤维的组装。两种变体的冷冻电镜结构表明，S477D 特异性地阻止了高活性组装界面的组装，仍然允许低活性 IMPDH1（546）纤维的组装。最后，我们发现 S477D 在细胞中发挥显性负效应，阻止内源性 IMPDH 纤维的组装。通过调节 IMPDH 的结构和高级组装，S477 磷酸化在黑暗中核苷酸周转率降低时作为下调视网膜 GTP 合成的机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/329c/10849882/08711706ec43/JCB_202310139_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/329c/10849882/d200e4665299/JCB_202310139_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/329c/10849882/ca578d6d3567/JCB_202310139_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/329c/10849882/ca956d19f15d/JCB_202310139_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/329c/10849882/0f8907ad6746/JCB_202310139_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/329c/10849882/9d9818037b8c/JCB_202310139_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/329c/10849882/52894f234ce8/JCB_202310139_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/329c/10849882/8d7da6f4b1ca/JCB_202310139_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/329c/10849882/0a116bea0a3a/JCB_202310139_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/329c/10849882/ab074cd0b73c/JCB_202310139_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/329c/10849882/98100485c7c7/JCB_202310139_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/329c/10849882/9327cdfdeae8/JCB_202310139_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/329c/10849882/716f2120c352/JCB_202310139_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/329c/10849882/08711706ec43/JCB_202310139_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/329c/10849882/d200e4665299/JCB_202310139_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/329c/10849882/ca578d6d3567/JCB_202310139_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/329c/10849882/ca956d19f15d/JCB_202310139_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/329c/10849882/0f8907ad6746/JCB_202310139_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/329c/10849882/9d9818037b8c/JCB_202310139_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/329c/10849882/52894f234ce8/JCB_202310139_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/329c/10849882/8d7da6f4b1ca/JCB_202310139_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/329c/10849882/0a116bea0a3a/JCB_202310139_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/329c/10849882/ab074cd0b73c/JCB_202310139_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/329c/10849882/98100485c7c7/JCB_202310139_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/329c/10849882/9327cdfdeae8/JCB_202310139_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/329c/10849882/716f2120c352/JCB_202310139_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/329c/10849882/08711706ec43/JCB_202310139_Fig8.jpg

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