| Structural highlights
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 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[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Twomey EC, Ji Z, Wales TE, Bodnar NO, Ficarro SB, Marto JA, Engen JR, Rapoport TA. Substrate processing by the Cdc48 ATPase complex is initiated by ubiquitin unfolding. Science. 2019 Jun 27. pii: science.aax1033. doi: 10.1126/science.aax1033. PMID:31249135 doi:http://dx.doi.org/10.1126/science.aax1033
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