Fig. 5: A model of PINK1 regulation by the Hsp90 machinery.

In its unfolded state, PINK1 is recognized and bound by Cdc37. The PINK1-Cdc37 complex is subsequently loaded onto the Hsp90 dimer in its open conformation. ATP binding to the N-terminal domains (NTDs) of the Hsp90 dimer induces conformational changes, resulting in the formation of a closed Hsp90-Cdc37-PINK1 complex and hydrolysis of the ATP molecules. Once PINK1 is fully loaded, Cdc37 dissociates, and FKBP51 enters the chaperone cycle. FKBP51 binds to the N-lobe of PINK1, promoting its proper folding. Upon completion of folding, FKBP51 dissociates from the complex, leaving the Hsp90- PINK1 maturation complex. Finally, upon release of ADP, the Hsp90 dimer opens, and the fully folded PINK1 is released into the cytoplasm. Cdc37 is shown in salmon, Hsp90 in cyan and blue, PINK1 in pink, and FKBP51 in blue-green.