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

Abstract 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 familial Parkinson’s disease. PINK1 is a high-affinity client of the HSP90–CDC37 complex and is stabilized by this chaperone system. However, the molecular mechanism by which HSP90–CDC37 facilitates the folding of PINK1 remains unclear. Here, we present a cryogenic electron microscopy structure of the human PINK1–HSP90–CDC37 complex. The β5 strand of the PINK1 N-lobe is accommodated in the central channel of 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 PINK1 N-helix. The HPNI motif of CDC37 interacts with the C-lobe of PINK1, mimicking the HPNI motif in the N-lobe. The pathogenic mutation L347P is suggested to disrupt these interactions, while H271Q is located within the HPNI motif in the N-lobe of PINK1. These findings provide structural insights into the folding of PINK1 and its dysfunction in Parkinson’s disease. Competing Interest Statement The authors have declared no competing interest. Footnotes The main text was edited to improve clarity. Figures were revised to correct labeling and enhance presentation.