Unique interface and dynamics of the complex of HSP90 with a specialized cochaperone AIPL1

Photoreceptor phosphodiesterase PDE6 is central for visual signal transduction. Maturation of PDE6 de-pends 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 A cryoelectron microscopy (cryo-EM) structure of the complex of HSP90 with AIPL1. This structure re-veals 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 pre-viously 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 frame-work for future structural studies of PDE6 maturation.

Automated summary

PDE6 is important for visual signal transduction and relies on the chaperone complex of HSP90 and AIPL1 for maturation. Disruption of PDE6 maturation leads to severe retina degeneration.