8dar | pdb_00008dar

Saccharomyces cerevisiae Ufd1/Npl4/Cdc48 complex unbound but in the presence of SUMO-ubiquitin(K48polyUb)-mEOS and ATP

Structural highlights

8dar is a 8 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 3Å
Ligands:	ADP, ATP, ZN
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

NPL4_YEAST Involved in the import of nuclear-targeted proteins into the nucleus and the export of poly(A) RNA out of the nucleus (PubMed:8930904, PubMed:11733065). Has a role in the endoplasmic reticulum-associated degradation (ERAD) pathway (PubMed:11739805, PubMed:11740563, PubMed:11847109). Required for the proteasome-dependent processing/activation of MGA2 and SPT23 transcription factors leading to the subsequent expression of OLE1 (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). Involved in spindle disassembly probably by promoting the degradation of spindle assemby factors ASE1 and CDC5 at the end of mitosis (PubMed:14636562).^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7]

Publication Abstract from PubMed

The Ufd1/Npl4/Cdc48 complex is a universal protein segregase that plays key roles in eukaryotic cellular processes. Its functions orchestrating the clearance or removal of polyubiquitylated targets are established; however, prior studies suggest that the complex also targets substrates modified by the ubiquitin-like protein SUMO. Here, we show that interactions between Ufd1 and SUMO enhance unfolding of substrates modified by SUMO-polyubiquitin hybrid chains by the budding yeast Ufd1/Npl4/Cdc48 complex compared to substrates modified by polyubiquitin chains, a difference that is accentuated when the complex has a choice between these substrates. Incubating Ufd1/Npl4/Cdc48 with a substrate modified by a SUMO-polyubiquitin hybrid chain produced a series of single-particle cryo-EM structures that reveal features of interactions between Ufd1/Npl4/Cdc48 and ubiquitin prior to and during unfolding of ubiquitin. These results are consistent with cellular functions for SUMO and ubiquitin modifications and support a physical model wherein Ufd1/Npl4/Cdc48, SUMO, and ubiquitin conjugation pathways converge to promote clearance of proteins modified with SUMO and polyubiquitin.

SUMO enhances unfolding of SUMO-polyubiquitin-modified substrates by the Ufd1/Npl4/Cdc48 complex.,Lee HG, Lemmon AA, Lima CD Proc Natl Acad Sci U S A. 2023 Jan 3;120(1):e2213703120. doi: , 10.1073/pnas.2213703120. Epub 2022 Dec 27. PMID:36574706^[8]

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
↑ Bays NW, Wilhovsky SK, Goradia A, Hodgkiss-Harlow K, Hampton RY. HRD4/NPL4 is required for the proteasomal processing of ubiquitinated ER proteins. Mol Biol Cell. 2001 Dec;12(12):4114-28. doi: 10.1091/mbc.12.12.4114. PMID:11739805 doi:https://dx.doi.org/10.1091/mbc.12.12.4114
↑ 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:https://dx.doi.org/10.1038/414652a
↑ 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
↑ 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:https://dx.doi.org/10.1016/j.molcel.2010.10.021
↑ DeHoratius C, Silver PA. Nuclear transport defects and nuclear envelope alterations are associated with mutation of the Saccharomyces cerevisiae NPL4 gene. Mol Biol Cell. 1996 Nov;7(11):1835-55. PMID:8930904
↑ Lee HG, Lemmon AA, Lima CD. SUMO enhances unfolding of SUMO-polyubiquitin-modified substrates by the Ufd1/Npl4/Cdc48 complex. Proc Natl Acad Sci U S A. 2023 Jan 3;120(1):e2213703120. PMID:36574706 doi:10.1073/pnas.2213703120

Proteopedia Page Contributors and Editors (what is this?)

OCA

[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] Bays NW, Wilhovsky SK, Goradia A, Hodgkiss-Harlow K, Hampton RY. HRD4/NPL4 is required for the proteasomal processing of ubiquitinated ER proteins. Mol Biol Cell. 2001 Dec;12(12):4114-28. doi: 10.1091/mbc.12.12.4114. PMID:11739805 doi:https://dx.doi.org/10.1091/mbc.12.12.4114

[3] 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:https://dx.doi.org/10.1038/414652a

[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] 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:https://dx.doi.org/10.1016/j.molcel.2010.10.021

[7] DeHoratius C, Silver PA. Nuclear transport defects and nuclear envelope alterations are associated with mutation of the Saccharomyces cerevisiae NPL4 gene. Mol Biol Cell. 1996 Nov;7(11):1835-55. PMID:8930904

[8] Lee HG, Lemmon AA, Lima CD. SUMO enhances unfolding of SUMO-polyubiquitin-modified substrates by the Ufd1/Npl4/Cdc48 complex. Proc Natl Acad Sci U S A. 2023 Jan 3;120(1):e2213703120. PMID:36574706 doi:10.1073/pnas.2213703120

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8dar | pdb_00008dar

Saccharomyces cerevisiae Ufd1/Npl4/Cdc48 complex unbound but in the presence of SUMO-ubiquitin(K48polyUb)-mEOS and ATP

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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