Structural organization of p62 filaments and the cellular ultrastructure of calcium-rich p62-enwrapped lipid droplet cargo

Sabrina Berkamp (), Lisa Jungbluth, Alexandros Katranidis, Siavash Mostafavi, Olivera Korculanin, Peng-Han Lu, Lotte Ickert, Maya M. Dierig, Lokesh Sharma, Lipi Thukral, Pitter F. Huesgen, Natalia L. Kononenko, Jörg Fitter, Rafal E. Dunin-Borkowski and Carsten Sachse ()
Additional contact information
Sabrina Berkamp: Forschungszentrum Jülich, Ernst-Ruska Centre for Microscopy and Spectroscopy with Electrons, ER-C-3/Structural Biology
Lisa Jungbluth: Forschungszentrum Jülich, Ernst-Ruska Centre for Microscopy and Spectroscopy with Electrons, ER-C-3/Structural Biology
Alexandros Katranidis: Forschungszentrum Jülich, Ernst-Ruska Centre for Microscopy and Spectroscopy with Electrons, ER-C-3/Structural Biology
Siavash Mostafavi: Forschungszentrum Jülich, Ernst-Ruska Centre for Microscopy and Spectroscopy with Electrons, ER-C-3/Structural Biology
Olivera Korculanin: Forschungszentrum Jülich, Ernst-Ruska Centre for Microscopy and Spectroscopy with Electrons, ER-C-3/Structural Biology
Peng-Han Lu: Forschungszentrum Jülich, Ernst-Ruska Centre for Microscopy and Spectroscopy with Electrons, ER-C-1/Physics of Nanoscale Systems
Lotte Ickert: Faculty of Medicine and University Hospital Cologne, CECAD Excellence Center & Center for Physiology and Pathophysiology
Maya M. Dierig: Schänzlestraße 1, Institute of Biology II, University of Freiburg
Lokesh Sharma: Mathura Road, Computational Structural Biology Lab, CSIR-Institute of Genomics and Integrative Biology
Lipi Thukral: Mathura Road, Computational Structural Biology Lab, CSIR-Institute of Genomics and Integrative Biology
Pitter F. Huesgen: Schänzlestraße 1, Institute of Biology II, University of Freiburg
Natalia L. Kononenko: Faculty of Medicine and University Hospital Cologne, CECAD Excellence Center & Center for Physiology and Pathophysiology
Jörg Fitter: Forschungszentrum Jülich, Ernst-Ruska Centre for Microscopy and Spectroscopy with Electrons, ER-C-3/Structural Biology
Rafal E. Dunin-Borkowski: Forschungszentrum Jülich, Ernst-Ruska Centre for Microscopy and Spectroscopy with Electrons, ER-C-1/Physics of Nanoscale Systems
Carsten Sachse: Forschungszentrum Jülich, Ernst-Ruska Centre for Microscopy and Spectroscopy with Electrons, ER-C-3/Structural Biology

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract The selective autophagy receptor p62/SQSTM1 is known to form higher-order filaments in vitro and to undergo liquid-liquid phase separation when mixed with poly-ubiquitin. Here, we determine the full-length cryo-EM structure of p62 and elucidate a structured double helical filament scaffold composed of the PB1-domain associated with the flexible C-terminal part and the solvent-accessible major groove. At different pH values and upon binding to soluble LC3, LC3-conjugated membranes and poly-ubiquitin, we observe p62 filament re-arrangements in the form of structural unwinding, disassembly, lateral association and bundling, respectively. In the cellular environment, under conditions of ATG5 knockdown leading to stalled autophagy, we imaged high-contrast layers consisting of p62 oligomers enwrapping lipid droplets by cryogenic electron tomography in situ, which we identified as calcium as well as phosphorus by compositional spectroscopy analysis. Together, we visualize the cellular ultrastructure of p62 oligomers with high calcium content as a potential early stage of autophagy.

Date: 2025
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DOI: 10.1038/s41467-025-66785-7

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