Department of Molecular Physiology and Biophysics, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
Department of Molecular Physiology and Biophysics, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
Structure. 2023 Mar 2;31(3):309-317.e5. doi: 10.1016/j.str.2022.12.014. Epub 2023 Jan 18.
Photoreceptor phosphodiesterase PDE6 is central for visual signal transduction. Maturation of PDE6 depends on a specialized chaperone complex of HSP90 with aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1). Disruption of PDE6 maturation underlies a severe form of retina degeneration. Here, we report a 3.9 Å cryoelectron microscopy (cryo-EM) structure of the complex of HSP90 with AIPL1. This structure reveals a unique interaction of the FK506-binding protein (FKBP)-like domain of AIPL1 with HSP90 at its dimer interface. Unusually, the N terminus AIPL1 inserts into the HSP90 lumen in a manner that was observed previously for HSP90 clients. Deletion of the 7 N-terminal residues of AIPL1 decreased its ability to cochaperone PDE6. Multi-body refinement of the cryo-EM data indicated large swing-like movements of AIPL1-FKBP. Modeling the complex of HSP90 with AIPL1 using crosslinking constraints indicated proximity of the mobile tetratricopeptide repeat (TPR) domain with the C-terminal domain of HSP90. Our study establishes a framework for future structural studies of PDE6 maturation.
光感受器磷酸二酯酶 PDE6 是视觉信号转导的核心。PDE6 的成熟依赖于 HSP90 与芳烃受体相互作用蛋白样 1 (AIPL1) 的特殊伴侣复合物。PDE6 成熟的破坏是一种严重的视网膜变性的基础。在这里，我们报告了 HSP90 与 AIPL1 复合物的 3.9Å 冷冻电镜 (cryo-EM) 结构。该结构揭示了 AIPL1 的 FK506 结合蛋白 (FKBP)-样结构域与 HSP90 二聚体界面的独特相互作用。不同寻常的是，AIPL1 的 N 端以以前在 HSP90 客户中观察到的方式插入 HSP90 腔中。AIPL1 的 7 个 N 端残基的缺失降低了其共伴侣 PDE6 的能力。冷冻电镜数据的多体精修表明 AIPL1-FKBP 发生了类似钟摆的大摆动运动。使用交联约束对 HSP90 与 AIPL1 的复合物进行建模表明，移动的四肽重复 (TPR) 结构域与 HSP90 的 C 端结构域接近。我们的研究为 PDE6 成熟的未来结构研究奠定了框架。
