Control of the guanylate cyclase signaling unit in phototransduction by the RD3 protein

RD3 蛋白对光转导中鸟苷酸环化酶信号单元的控制

• 批准号: 190739534
• 负责人: Professor Dr. Karl-Wilhelm Koch
• 金额: --
• 依托单位: Institut für Biologie und Umweltwissenschaften (IBU)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/190739534?language=en
• 关键词: Control; guanylate; cyclase; signaling; unit

Rod and cone photoreceptor cells operate by a fine-balanced homeostasis of two intracellular second messengers, guanosine-3´,5´-cyclic monophosphate (cyclic GMP) and calcium. Cyclic GMP is synthesized by a membrane bound guanylate cyclase and dysregulation of cyclic GMP signaling can cause degeneration of photoreceptor cells. Several forms of hereditary retinal dystrophies like Leber congenital amaurosis, cone-rod dystrophies and retinitis pigmentosa correlate with mutations in the genes of guanylate cyclase and its regulatory proteins named GCAPs. Recent evidence suggests that a protein named RD3 has a crucial role in maintaining photoreceptor function by controlling one of its key signaling units, the guanylate cyclase/ GCAP complex. The aim of the present project is to investigate how the RD3 protein interacts with dystrophy relevant mutants of guanylate cyclase, whether it stabilizes structurally labile forms of some of these mutants, and how it controls their trafficking out of the endoplasmic reticulum. Furthermore, it is planned to investigate how constitutively active mutants of the guanylate cyclase activator GCAP1, which cause cone dystrophies, are influenced by co-expression of and association with the RD3 protein. Finally, the molecular and protein-chemical properties of the RD3 protein itself are not well understood and the project will further focus on structure-function relationships of RD3 and RD3 mutants. Within this framework we will also test the hypothesis, whether a posttranslational modification like phosphorylation of RD3 controls the direct interaction with the cyclic GMP signaling unit. We expect from our studies a deeper understanding of the molecular mechanisms leading to retinal degeneration involving the RD3 protein and its mutual dependencies with the guanylate cyclase complex.

视杆细胞和视锥细胞由两个细胞内的第二信使--鸟苷-3‘，5’-环一磷酸(CGMP)和钙--的平衡平衡运行。环状GMP是由膜结合的鸟苷环化酶合成的，环状GMP信号的失调可导致光感受器细胞的退化。几种形式的遗传性视网膜营养不良，如Leber先天性黑色素、视锥视杆细胞营养不良和视网膜色素变性，都与鸟苷环化酶基因及其调控蛋白GCAPs的突变有关。最近的证据表明，一种名为RD3的蛋白质通过控制其关键信号单位之一鸟苷环化酶/GCAP复合体，在维持光感受器功能方面发挥着至关重要的作用。本项目的目的是研究RD3蛋白是如何与鸟苷酸环化酶营养不良相关突变体相互作用的，它是否稳定了其中一些突变体的结构不稳定形式，以及它是如何控制它们运输出内质网的。此外，还计划研究引起锥体营养不良的鸟苷环化酶激活剂GCAP1的结构性活性突变是如何受到RD3蛋白的共表达和关联的影响。最后，RD3蛋白本身的分子和蛋白质化学性质还不是很清楚，该项目将进一步关注RD3和RD3突变体的结构-功能关系。在这个框架内，我们还将检验假设，是否翻译后修饰，如RD3的磷酸化控制与循环GMP信号单位的直接相互作用。我们希望从我们的研究中更深入地了解导致视网膜变性的分子机制，包括RD3蛋白及其与鸟苷环化酶复合体的相互依赖。

项目成果

Dysfunction of cGMP signalling in photoreceptors by a macular dystrophy-related mutation in the calcium sensor GCAP1

• DOI: 10.1093/hmg/ddw374
• 发表时间: 2016-12
• 期刊: Human Molecular Genetics
• 影响因子: 3.5
• 作者: Farina Vocke;N. Weisschuh;V. Marino;Silvia Malfatti;S. Jacobson;Charlotte M. Reiff;D. Dell’Orco;K. Koch

Control of the Nucleotide Cycle in Photoreceptor Cell Extracts by Retinal Degeneration Protein 3

视网膜变性蛋白 3 控制感光细胞提取物中的核苷酸循环

• DOI: 10.3389/fnmol.2018.00052
• 发表时间: 2018
• 期刊: Frontiers in Molecular Neuroscience
• 影响因子: 4.8
• 作者: Wimberg;Janssen-Bienhold
• 通讯作者: Janssen-Bienhold

Photoreceptor calcium sensor proteins in detergent-resistant membrane rafts are regulated via binding to caveolin-1.

耐洗涤剂膜筏中的光感受器钙传感器蛋白通过与 Caveolin-1 结合进行调节

• DOI: 10.1016/j.ceca.2018.04.003
• 发表时间: 2018
• 期刊: Cell calcium
• 影响因子: 4
• 作者: Vladimirova;Zernii;Baksheeva;Wimberg;Kazakov;Tikhomirova;Nemashkalova;Mitkevich;Zamyatnin Jr;Lipkin;Philippov;Permyakov;Zinchenko
• 通讯作者: Zinchenko

Photoreceptor Guanylate Cyclase (GUCY2D) Mutations Cause Retinal Dystrophies by Severe Malfunction of Ca2+-Dependent Cyclic GMP Synthesis

光感受器鸟苷酸环化酶 (GUCY2D) 突变通过 Ca2 依赖性环状 GMP 合成的严重功能障碍导致视网膜营养不良

• DOI: 10.3389/fnmol.2018.00348
• 发表时间: 2018
• 期刊: Frontiers in Molecular Neuroscience
• 影响因子: 4.8
• 作者: Wimberg;Yosovich;Namburi;Sharon
• 通讯作者: Sharon