Singh Sneha, Srivastava Dhiraj, Boyd Kimberly, Artemyev Nikolai O
Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52242.
Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, Iowa City, IA 52242.
Proc Natl Acad Sci U S A. 2025 Jan 7;122(1):e2419732121. doi: 10.1073/pnas.2419732121. Epub 2024 Dec 31.
Cone cGMP-phosphodiesterase (PDE6) is the key effector enzyme for daylight vision, and its properties are critical for shaping distinct physiology of cone photoreceptors. We determined the structures of human cone PDE6C in various liganded states by single-particle cryo-EM that reveal essential functional dynamics and adaptations of the enzyme. Our analysis exposed the dynamic nature of PDE6C association with its regulatory γ-subunit (Pγ) which allows openings of the catalytic pocket in the absence of phototransduction signaling, thereby controlling photoreceptor noise and sensitivity. We demonstrate evolutionarily recent adaptations of PDE6C stemming from residue substitutions in the Pγ subunit and the noncatalytic cGMP binding site and influencing the Pγ dynamics in holoPDE6C. Thus, our structural analysis sheds light on the previously unrecognized molecular evolution of the effector enzyme in cones that advances adaptation for photopic vision.
视锥细胞环鸟苷酸磷酸二酯酶（PDE6）是明视觉的关键效应酶，其特性对于塑造视锥光感受器独特的生理功能至关重要。我们通过单颗粒冷冻电镜确定了处于各种配体结合状态的人视锥PDE6C的结构，这些结构揭示了该酶基本的功能动力学和适应性变化。我们的分析揭示了PDE6C与其调节性γ亚基（Pγ）结合的动态性质，这使得催化口袋在没有光转导信号时能够打开，从而控制光感受器的噪声和敏感性。我们证明了PDE6C在进化上最近的适应性变化源于Pγ亚基和非催化性环鸟苷酸结合位点的残基替换，并影响全酶PDE6C中Pγ的动力学。因此，我们的结构分析揭示了视锥细胞中效应酶此前未被认识的分子进化，这推动了对明视觉的适应性变化。
