Structural basis of p62/SQSTM1 helical filaments, their presence in p62 bodies and role in cargo recognition in the cell
Structural basis of p62/SQSTM1 helical filaments, their presence in p62 bodies and role in cargo recognition in the cell
Abstract p62/SQSTM1 is an autophagy receptor and signaling adaptor with an N-terminal PB1 domain that forms the scaffold of phase-separated p62 bodies in the cell. The molecular determinants that govern PB1 domain filament formation in vitro remain to be determined and the role of p62 filaments inside the cell is currently unclear. We determined four high-resolution cryo-EM structures of different human and Arabidopsis PB1 domain assemblies and observed a filamentous ultrastructure of phase-separated p62/SQSTM1 bodies using correlative cellular EM. We show that oligomerization or polymerization, driven by a double arginine finger in the PB1 domain, is a general requirement for lysosomal targeting of p62. Furthermore, the filamentous assembly state of p62 is required for autophagosomal processing of the p62-specific cargo KEAP1. Our results show that using such mechanisms, p62 filaments can be critical for cargo recognition and are an integral part of phase separated p62 bodies.
Jakobi Arjen J.、Schultz Sebastian W.、Palara Anthimi、Kuhm Tanja、Shrestha Birendra Kumar、Wilmanns Matthias、Brech Andreas、Huber Stefan T.、Hagen Wim J.H.、Sachse Carsten、Mortensen Simon A.、Johansen Terje、Lamark Trond
European Molecular Biology Laboratory (EMBL), Structural and Computational Biology Unit||European Molecular Biology Laboratory (EMBL), Hamburg Unit c/o DESY||The Hamburg Centre for Ultrafast Imaging (CUI)Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University HospitalMolecular Cancer Research Group, Institute of Medical Biology, University of Troms? ¨C The Arctic University of NorwayEuropean Molecular Biology Laboratory (EMBL), Structural and Computational Biology UnitMolecular Cancer Research Group, Institute of Medical Biology, University of Troms? ¨C The Arctic University of NorwayEuropean Molecular Biology Laboratory (EMBL), Hamburg Unit c/o DESY||The Hamburg Centre for Ultrafast Imaging (CUI)Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University HospitalEuropean Molecular Biology Laboratory (EMBL), Structural and Computational Biology UnitEuropean Molecular Biology Laboratory (EMBL), Structural and Computational Biology UnitEuropean Molecular Biology Laboratory (EMBL), Structural and Computational Biology Unit||Ernst-Ruska Centre for Microscopy and Spectroscopy with Electrons (ER-C-3/Structural Biology)||JuStruct: J¨1lich Center for Structural BiologyEuropean Molecular Biology Laboratory (EMBL), Structural and Computational Biology Unit||Ernst-Ruska Centre for Microscopy and Spectroscopy with Electrons (ER-C-3/Structural Biology)||JuStruct: J¨1lich Center for Structural BiologyMolecular Cancer Research Group, Institute of Medical Biology, University of Troms? ¨C The Arctic University of NorwayMolecular Cancer Research Group, Institute of Medical Biology, University of Troms? ¨C The Arctic University of Norway
细胞生物学分子生物学生物化学
PB1 domainp62/SQSTM1helical filamentsp62 bodiesphase separationcargo recognitionautophagy
Jakobi Arjen J.,Schultz Sebastian W.,Palara Anthimi,Kuhm Tanja,Shrestha Birendra Kumar,Wilmanns Matthias,Brech Andreas,Huber Stefan T.,Hagen Wim J.H.,Sachse Carsten,Mortensen Simon A.,Johansen Terje,Lamark Trond.Structural basis of p62/SQSTM1 helical filaments, their presence in p62 bodies and role in cargo recognition in the cell[EB/OL].(2025-03-28)[2025-08-04].https://www.biorxiv.org/content/10.1101/671792.点此复制
评论