Molecular mechanism of PINK1 regulation by the Hsp90 machinery

Xuyang Tian, Jiayue Su, Ziyi Wang, Tao Liu, Huifang Xiong, Shan Sun, Kunrong Mei () and Sen-Fang Sui ()
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Xuyang Tian: Tsinghua University, State Key Laboratory of Membrane Biology, Beijing Frontier Research Center for Biological Structure, School of Life Sciences
Jiayue Su: Tsinghua University, State Key Laboratory of Membrane Biology, Beijing Frontier Research Center for Biological Structure, School of Life Sciences
Ziyi Wang: Tsinghua University, State Key Laboratory of Membrane Biology, Beijing Frontier Research Center for Biological Structure, School of Life Sciences
Tao Liu: Tsinghua University, State Key Laboratory of Membrane Biology, Beijing Frontier Research Center for Biological Structure, School of Life Sciences
Huifang Xiong: Tianjin University, School of Pharmaceutical Science and Technology, Faculty of Medicine
Shan Sun: Tsinghua University, State Key Laboratory of Membrane Biology, Beijing Frontier Research Center for Biological Structure, School of Life Sciences
Kunrong Mei: Tianjin University, School of Pharmaceutical Science and Technology, Faculty of Medicine
Sen-Fang Sui: Tsinghua University, State Key Laboratory of Membrane Biology, Beijing Frontier Research Center for Biological Structure, School of Life Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: Abstract Hundreds of human kinases, including PINK1—a protein kinase associated with familial Parkinson’s disease—are regulated by Hsp90 and its cochaperones. While previous studies have elucidated the mechanism of kinase loading into the Hsp90 machinery, the subsequent regulation of kinases by Hsp90 and its cochaperones remains poorly understood. In this study, using complexes obtained through PINK1 pulldown, we determine the cryo-EM structures of the human Hsp90-Cdc37-PINK1 complex at 2.84 Å, Hsp90-FKBP51-PINK1 at approximately 6 Å, and Hsp90- PINK1 at 2.98 Å. These structures, along with the bound nucleotide in the Hsp90 dimers of the three complexes, provide insights into the Hsp90 chaperone machinery for kinases and elucidate the molecular mechanisms governing cytosolic PINK1 regulation.

Date: 2025
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DOI: 10.1038/s41467-025-65859-w

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