Structural basis for the folding of PINK1 by the HSP90–CDC37 chaperone complex

PTEN-induced kinase 1 (PINK1) is a mitochondrial serine/threonine kinase that plays a central role in Parkin-dependent mitophagy. Mutations in PINK1 are associated with autosomal recessive forms of Parkinson′s disease. PINK1 is identified as a high-affinity client of the HSP90–CDC37 complex. Stability of PINK1 is regulated by the HSP90–CDC37 chaperone system. However, the molecular mechanism by which HSP90–CDC37 recognizes and facilitate the folding of PINK1 remains unclear. Here, we present a cryogenic electron microscopy (cryo-EM) structure of the human PINK1–HSP90–CDC37 complex. The β5 strand of the PINK1 N-lobe projects into the central channel formed at the interface between two protomers in the HSP90 dimer, which holds the PINK1 kinase domain in a partially unfolded state. The C-lobe and unique C-terminal extension (CTE) of PINK1 is folded. HSP90 covers the CTE of PINK1, which overlaps with interaction sites for TOM5, TOM20, and the intramolecular N-helix. The HPNI motif of CDC37 interacts with the C-lobe of PINK1, mimicking the HPNI motif in the N-lobe of PINK1. A pathogenic mutation L347P is suggested to disrupt the interaction with the HPNI motif of CDC37. Another pathogenic mutation H271Q is located within the HPNI motif of the N-lobe of PINK1. These findings provide structural insights into the folding of PINK1 and its dysfunction in Parkinson′s disease.