Structural and functional dynamics of human cone cGMP- phosphodiesterase important for photopic vision

• 成果类型: Article
• 署名作者: Singh, Sneha; Srivastava, Dhiraj; Boyd, Kimberly; Artemyev, Nikolai O.
• 署名单位: University of Iowa; University of Iowa
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12158
• DOI: 10.1073/pnas.2419732121
• 发表日期: 2024-01-07
• 关键词: cryo-em; catalytic subunits; crystal-structure; binding-sites; high-affinity; gaf domains; rod; pde6; inhibition; transducin

摘要

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 gamma- subunit (P gamma) 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 P gamma subunit and the noncatalytic cGMP binding site and influencing the P gamma 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.