6oab

Cdc48-Npl4 complex processing poly-ubiquitinated substrate in the presence of ADP-BeFx, state 2

Loading... Status: waiting for Mol* initialization Structural highlights 6oab is a 6 chain structure with sequence from Saccharomyces cerevisiae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.6Å Ligands: ADP, BEF Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function CDC48_YEAST ATP-dependent chaperone which probably uses the energy provided by ATP hydrolysis to generate mechanical force to unfold substrate proteins, disassemble protein complexes, and disaggregate protein aggregates (PubMed:21454554). By recruiting and promoting the degradation of ubiquitinated proteins, plays a role in the ubiquitin fusion degradation (UFD) pathway (PubMed:16428438). Has a role in the endoplasmic reticulum-associated degradation (ERAD) pathway which mediates the cytoplasmic elimination of misfolded proteins exported from the ER (PubMed:11813000, PubMed:11740563, PubMed:11847109, PubMed:21148305). Required for the proteasome-dependent processing/activation of MGA2 and SPT23 transcription factors leading to the subsequent expression of OLE1 (PubMed:11847109, PubMed:11733065). Has an additional role in the turnover of OLE1 where it targets ubiquitinated OLE1 and other proteins to the ERAD (PubMed:11847109). Regulates ubiquitin-mediated mitochondria protein degradation (PubMed:21070972, PubMed:27044889). Involved in spindle disassembly probably by promoting the degradation of spindle assembly factors ASE1 and CDC5 at the end of mitosis (PubMed:14636562). Component of the ribosome quality control complex (RQC), a ribosome-associated complex that mediates ubiquitination and extraction of incompletely synthesized nascent chains for proteasomal degradation (PubMed:23178123, PubMed:24261871). CDC48 may provide the mechanical force that dislodges the polyubiquitinated nascent peptides from the exit channel (PubMed:23178123, PubMed:24261871). Required for ribophagy, a process which relocalizes ribosomal particles into the vacuole for degradation in response to starvation (PubMed:20508643). Publication Abstract from PubMed The Cdc48 ATPase (p97 or VCP in mammals) and its cofactor Ufd1/Npl4 extract poly-ubiquitinated proteins from membranes or macromolecular complexes for subsequent degradation by the proteasome. How Cdc48 processes its diverse and often well-folded substrates is unclear. Here, we report cryo-EM structures of the Cdc48 ATPase in complex with Ufd1/Npl4 and poly-ubiquitinated substrate. The structures show that the Cdc48 complex initiates substrate processing by unfolding a ubiquitin molecule. The unfolded ubiquitin molecule binds to Npl4 and projects its N-terminal segment through both hexameric ATPase rings. Pore loops of the second ring form a staircase that acts as a conveyer belt to move the polypeptide through the central pore. Inducing the unfolding of ubiquitin allows the Cdc48 ATPase complex to process a broad range of substrates. Substrate processing by the Cdc48 ATPase complex is initiated by ubiquitin unfolding.,Twomey EC, Ji Z, Wales TE, Bodnar NO, Ficarro SB, Marto JA, Engen JR, Rapoport TA Science. 2019 Jun 27. pii: science.aax1033. doi: 10.1126/science.aax1033. PMID:31249135 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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