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 Parkinsons 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 {beta}5 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 Parkinsons disease.