8ub4

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Cdc48-Shp1 unfolding native substrate, consensus structureCdc48-Shp1 unfolding native substrate, consensus structure

Structural highlights

8ub4 is a 10 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 2.9Å
Ligands:, ,
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).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]

Publication Abstract from PubMed

The Cdc48 AAA+ ATPase is an abundant and essential enzyme that unfolds substrates in multiple protein quality control pathways. The enzyme includes two conserved AAA+ ATPase motor domains, D1 and D2, that assemble as hexameric rings with D1 stacked above D2. Here, we report an ensemble of native structures of Cdc48 affinity purified from budding yeast lysate in complex with the adaptor Shp1 in the act of unfolding substrate. Our analysis reveals a continuum of structural snapshots that spans the entire translocation cycle. These data uncover elements of Shp1-Cdc48 interactions and support a 'hand-over-hand' mechanism in which the sequential movement of individual subunits is closely coordinated. D1 hydrolyzes ATP and disengages from substrate prior to D2, while D2 rebinds ATP and re-engages with substrate prior to D1, thereby explaining the dominant role played by the D2 motor in substrate translocation/unfolding.

Visualization of the Cdc48 AAA+ ATPase protein unfolding pathway.,Cooney I, Schubert HL, Cedeno K, Fisher ON, Carson R, Price JC, Hill CP, Shen PS Nat Commun. 2024 Aug 29;15(1):7505. doi: 10.1038/s41467-024-51835-3. PMID:39209885[14]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Rape M, Hoppe T, Gorr I, Kalocay M, Richly H, Jentsch S. Mobilization of processed, membrane-tethered SPT23 transcription factor by CDC48(UFD1/NPL4), a ubiquitin-selective chaperone. Cell. 2001 Nov 30;107(5):667-77. PMID:11733065
  2. ↑ Ye Y, Meyer HH, Rapoport TA. The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol. Nature. 2001 Dec 6;414(6864):652-6. PMID:11740563 doi:http://dx.doi.org/10.1038/414652a
  3. ↑ Jarosch E, Taxis C, Volkwein C, Bordallo J, Finley D, Wolf DH, Sommer T. Protein dislocation from the ER requires polyubiquitination and the AAA-ATPase Cdc48. Nat Cell Biol. 2002 Feb;4(2):134-9. PMID:11813000 doi:http://dx.doi.org/10.1038/ncb746
  4. ↑ Braun S, Matuschewski K, Rape M, Thoms S, Jentsch S. Role of the ubiquitin-selective CDC48(UFD1/NPL4 )chaperone (segregase) in ERAD of OLE1 and other substrates. EMBO J. 2002 Feb 15;21(4):615-21. PMID:11847109
  5. ↑ Cao K, Nakajima R, Meyer HH, Zheng Y. The AAA-ATPase Cdc48/p97 regulates spindle disassembly at the end of mitosis. Cell. 2003 Oct 31;115(3):355-67. PMID:14636562
  6. ↑ Mullally JE, Chernova T, Wilkinson KD. Doa1 is a Cdc48 adapter that possesses a novel ubiquitin binding domain. Mol Cell Biol. 2006 Feb;26(3):822-30. doi: 10.1128/MCB.26.3.822-830.2006. PMID:16428438 doi:http://dx.doi.org/10.1128/MCB.26.3.822-830.2006
  7. ↑ Ossareh-Nazari B, Bonizec M, Cohen M, Dokudovskaya S, Delalande F, Schaeffer C, Van Dorsselaer A, Dargemont C. Cdc48 and Ufd3, new partners of the ubiquitin protease Ubp3, are required for ribophagy. EMBO Rep. 2010 Jul;11(7):548-54. doi: 10.1038/embor.2010.74. Epub 2010 May 28. PMID:20508643 doi:http://dx.doi.org/10.1038/embor.2010.74
  8. ↑ Heo JM, Livnat-Levanon N, Taylor EB, Jones KT, Dephoure N, Ring J, Xie J, Brodsky JL, Madeo F, Gygi SP, Ashrafi K, Glickman MH, Rutter J. A stress-responsive system for mitochondrial protein degradation. Mol Cell. 2010 Nov 12;40(3):465-80. doi: 10.1016/j.molcel.2010.10.021. PMID:21070972 doi:http://dx.doi.org/10.1016/j.molcel.2010.10.021
  9. ↑ Tran JR, Tomsic LR, Brodsky JL. A Cdc48p-associated factor modulates endoplasmic reticulum-associated degradation, cell stress, and ubiquitinated protein homeostasis. J Biol Chem. 2011 Feb 18;286(7):5744-55. doi: 10.1074/jbc.M110.179259. Epub 2010 , Dec 9. PMID:21148305 doi:http://dx.doi.org/10.1074/jbc.M110.179259
  10. ↑ Nishikori S, Esaki M, Yamanaka K, Sugimoto S, Ogura T. Positive cooperativity of the p97 AAA ATPase is critical for essential functions. J Biol Chem. 2011 May 6;286(18):15815-20. doi: 10.1074/jbc.M110.201400. Epub 2011, Mar 18. PMID:21454554 doi:http://dx.doi.org/10.1074/jbc.M110.201400
  11. ↑ Brandman O, Stewart-Ornstein J, Wong D, Larson A, Williams CC, Li GW, Zhou S, King D, Shen PS, Weibezahn J, Dunn JG, Rouskin S, Inada T, Frost A, Weissman JS. A ribosome-bound quality control complex triggers degradation of nascent peptides and signals translation stress. Cell. 2012 Nov 21;151(5):1042-54. doi: 10.1016/j.cell.2012.10.044. PMID:23178123 doi:http://dx.doi.org/10.1016/j.cell.2012.10.044
  12. ↑ Matsuda R, Ikeuchi K, Nomura S, Inada T. Protein quality control systems associated with no-go and nonstop mRNA surveillance in yeast. Genes Cells. 2014 Jan;19(1):1-12. doi: 10.1111/gtc.12106. Epub 2013 Nov 21. PMID:24261871 doi:http://dx.doi.org/10.1111/gtc.12106
  13. ↑ Wu X, Li L, Jiang H. Doa1 targets ubiquitinated substrates for mitochondria-associated degradation. J Cell Biol. 2016 Apr 11;213(1):49-63. doi: 10.1083/jcb.201510098. Epub 2016 Apr , 4. PMID:27044889 doi:http://dx.doi.org/10.1083/jcb.201510098
  14. ↑ Cooney I, Schubert HL, Cedeno K, Fisher ON, Carson R, Price JC, Hill CP, Shen PS. Visualization of the Cdc48 AAA+ ATPase protein unfolding pathway. Nat Commun. 2024 Aug 29;15(1):7505. PMID:39209885 doi:10.1038/s41467-024-51835-3

8ub4, resolution 2.90Å

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