PDF(Pubmed)
Abstract：
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.
摘要：
光感受器磷酸二酯酶PDE6是视觉信号转导的核心。PDE6的成熟取决于HSP90与芳基烃受体相互作用蛋白样1（AIPL1）的特殊伴侣复合物。PDE6成熟的中断是严重形式的视网膜变性的基础。这里,我们报告了HSP90与AIPL1的复合物的3.9进行低温电子显微镜（cryo-EM）结构。该结构揭示了AIPL1的FK506结合蛋白（FKBP）样结构域与HSP90在其二聚体界面处的独特相互作用。通常情况下，N末端AIPL1以以前在HSP90患者中观察到的方式插入HSP90管腔。AIPL1的7个N末端残基的缺失降低了其与伴侣PDE6的能力。低温EM数据的多体细化表明AIPL1-FKBP的大的摆动状运动。使用交联约束对HSP90与AIPL1的复合物进行建模，表明移动四三肽重复序列（TPR）结构域与HSP90的C末端结构域接近。我们的研究为未来PDE6成熟的结构研究建立了框架。
