6tgy

Cryo-EM structure of p62-PB1 filament (L-type)

Loading... Status: waiting for Mol* initialization Structural highlights 6tgy is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.5Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease SQSTM_HUMAN Defects in SQSTM1 are a cause of Paget disease of bone (PDB) [MIM:602080. PDB is a metabolic bone disease affecting the axial skeleton and characterized by focal areas of increased and disorganized bone turn-over due to activated osteoclasts. Manifestations of the disease include bone pain, deformity, pathological fractures, deafness, neurological complications and increased risk of osteosarcoma. PDB is a chronic disease affecting 2 to 3% of the population above the age of 40 years. Note=In a cell model for Huntington disease (HD), appears to form a shell surrounding aggregates of mutant HTT that may protect cells from apoptosis, possibly by recruiting autophagosomal components to the polyubiquitinylated protein aggregates. Function SQSTM_HUMAN Required both for the formation and autophagic degradation of polyubiquitin-containing bodies, called ALIS (aggresome-like induced structures). Links ALIS to the autophagic machinery via direct interaction with MAP1 LC3 family members. May regulate the activation of NFKB1 by TNF-alpha, nerve growth factor (NGF) and interleukin-1. May play a role in titin/TTN downstream signaling in muscle cells. May regulate signaling cascades through ubiquitination. Adapter that mediates the interaction between TRAF6 and CYLD (By similarity). May be involved in cell differentiation, apoptosis, immune response and regulation of K(+) channels. Publication Abstract from PubMed 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 here determine four high-resolution cryo-EM structures of different human and Arabidopsis PB1 domain assemblies and observed a filamentous ultrastructure of 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 uptake in autophagy and are an integral part of phase-separated p62 bodies. Structural basis of p62/SQSTM1 helical filaments and their role in cellular cargo uptake.,Jakobi AJ, Huber ST, Mortensen SA, Schultz SW, Palara A, Kuhm T, Shrestha BK, Lamark T, Hagen WJH, Wilmanns M, Johansen T, Brech A, Sachse C Nat Commun. 2020 Jan 23;11(1):440. doi: 10.1038/s41467-020-14343-8. PMID:31974402 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Sequestosome

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