A Mighty "Protein Extractor" of the Cell: Structure and Function of the P97/CDC48 ATPase

Overview

Journal Front Mol Biosci

Specialty Biology

Date 2017 Jun 30

PMID 28660197

Citations 100

Authors

Yihong Ye

Wai Kwan Tang

Ting Zhang

Di Xia

Affiliations

Soon will be listed here.

Abstract

p97/VCP (known as Cdc48 in or TER94 in ) is one of the most abundant cytosolic ATPases. It is highly conserved from archaebacteria to eukaryotes. In conjunction with a large number of cofactors and adaptors, it couples ATP hydrolysis to segregation of polypeptides from immobile cellular structures such as protein assemblies, membranes, ribosome, and chromatin. This often results in proteasomal degradation of extracted polypeptides. Given the diversity of p97 substrates, this "segregase" activity has profound influence on cellular physiology ranging from protein homeostasis to DNA lesion sensing, and mutations in p97 have been linked to several human diseases. Here we summarize our current understanding of the structure and function of this important cellular machinery and discuss the relevant clinical implications.

Citing Articles

p97 Inhibitors Possessing Antiviral Activity Against SARS-CoV-2 and Low Cytotoxicity.

Ding R, Edwards T, Goswami P, Wilson D, Dreis C, Ye Y Pharmaceuticals (Basel). 2025; 18(1.

PMID: 39861192 PMC: 11768289. DOI: 10.3390/ph18010131.

A face-off between Smaug and Caspar modulates primordial germ cell count and identity in embryos.

Deshpande G, Das S, Roy A, Ratnaparkhi G Fly (Austin). 2024; 19(1):2438473.

PMID: 39718186 PMC: 11702937. DOI: 10.1080/19336934.2024.2438473.

ATPase Valosin-Containing Protein (VCP) Is Involved During the Replication and Egress of Sialodacryoadenitis Virus (SDAV) in Neurons.

Bartak M, Krahel W, Chodkowski M, Grel H, Walczak J, Pallepati A Int J Mol Sci. 2024; 25(21).

PMID: 39519185 PMC: 11546310. DOI: 10.3390/ijms252111633.

Mechanisms and regulation of substrate degradation by the 26S proteasome.

Arkinson C, Dong K, Gee C, Martin A Nat Rev Mol Cell Biol. 2024; 26(2):104-122.

PMID: 39362999 PMC: 11772106. DOI: 10.1038/s41580-024-00778-0.

Visualization of the Cdc48 AAA+ ATPase protein unfolding pathway.

Cooney I, Schubert H, Cedeno K, Fisher O, Carson R, Price J Nat Commun. 2024; 15(1):7505.

PMID: 39209885 PMC: 11362554. DOI: 10.1038/s41467-024-51835-3.

References

Koegl M, Hoppe T, Schlenker S, Ulrich H, Mayer T, Jentsch S . A novel ubiquitination factor, E4, is involved in multiubiquitin chain assembly. Cell. 1999; 96(5):635-44. DOI: 10.1016/s0092-8674(00)80574-7. View

Meyer H, Shorter J, Seemann J, Pappin D, Warren G . A complex of mammalian ufd1 and npl4 links the AAA-ATPase, p97, to ubiquitin and nuclear transport pathways. EMBO J. 2000; 19(10):2181-92. PMC: 384367. DOI: 10.1093/emboj/19.10.2181. View

Singh S, GRIMAUD R, Hoskins J, Wickner S, Maurizi M . Unfolding and internalization of proteins by the ATP-dependent proteases ClpXP and ClpAP. Proc Natl Acad Sci U S A. 2000; 97(16):8898-903. PMC: 16793. DOI: 10.1073/pnas.97.16.8898. View

Roy L, Bergeron J, Lavoie C, Hendriks R, Gushue J, Fazel A . Role of p97 and syntaxin 5 in the assembly of transitional endoplasmic reticulum. Mol Biol Cell. 2000; 11(8):2529-42. PMC: 14937. DOI: 10.1091/mbc.11.8.2529. View

Bays N, Gardner R, Seelig L, Joazeiro C, Hampton R . Hrd1p/Der3p is a membrane-anchored ubiquitin ligase required for ER-associated degradation. Nat Cell Biol. 2001; 3(1):24-9. DOI: 10.1038/35050524. View

Zhang X, Shaw A, Bates P, NEWMAN R, Gowen B, Orlova E . Structure of the AAA ATPase p97. Mol Cell. 2001; 6(6):1473-84. DOI: 10.1016/s1097-2765(00)00143-x. View

Rouiller I, Butel V, Latterich M, Milligan R . A major conformational change in p97 AAA ATPase upon ATP binding. Mol Cell. 2001; 6(6):1485-90. DOI: 10.1016/s1097-2765(00)00144-1. View

Buchberger A, Howard M, Proctor M, Bycroft M . The UBX domain: a widespread ubiquitin-like module. J Mol Biol. 2001; 307(1):17-24. DOI: 10.1006/jmbi.2000.4462. View

Kimonis V, Kovach M, Waggoner B, Leal S, Salam A, RIMER L . Clinical and molecular studies in a unique family with autosomal dominant limb-girdle muscular dystrophy and Paget disease of bone. Genet Med. 2001; 2(4):232-41. PMC: 6173187. DOI: 10.1097/00125817-200007000-00006. View

10.

Ogura T, Wilkinson A . AAA+ superfamily ATPases: common structure--diverse function. Genes Cells. 2001; 6(7):575-97. DOI: 10.1046/j.1365-2443.2001.00447.x. View

11.

Yuan X, Shaw A, Zhang X, Kondo H, Lally J, Freemont P . Solution structure and interaction surface of the C-terminal domain from p47: a major p97-cofactor involved in SNARE disassembly. J Mol Biol. 2001; 311(2):255-63. DOI: 10.1006/jmbi.2001.4864. View

12.

Hitchcock A, Krebber H, Frietze S, Lin A, Latterich M, Silver P . The conserved npl4 protein complex mediates proteasome-dependent membrane-bound transcription factor activation. Mol Biol Cell. 2001; 12(10):3226-41. PMC: 60169. DOI: 10.1091/mbc.12.10.3226. View

13.

Fang S, Ferrone M, Yang C, Jensen J, Tiwari S, Weissman A . The tumor autocrine motility factor receptor, gp78, is a ubiquitin protein ligase implicated in degradation from the endoplasmic reticulum. Proc Natl Acad Sci U S A. 2001; 98(25):14422-7. PMC: 64697. DOI: 10.1073/pnas.251401598. View

14.

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; 107(5):667-77. DOI: 10.1016/s0092-8674(01)00595-5. View

15.

Bays N, Wilhovsky S, Goradia A, Hampton R . HRD4/NPL4 is required for the proteasomal processing of ubiquitinated ER proteins. Mol Biol Cell. 2001; 12(12):4114-28. PMC: 60780. DOI: 10.1091/mbc.12.12.4114. View

16.

Ye Y, Meyer H, Rapoport T . The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol. Nature. 2001; 414(6864):652-6. DOI: 10.1038/414652a. View

17.

Rabinovich E, Kerem A, Frohlich K, Diamant N, Bar-Nun S . AAA-ATPase p97/Cdc48p, a cytosolic chaperone required for endoplasmic reticulum-associated protein degradation. Mol Cell Biol. 2002; 22(2):626-34. PMC: 139744. DOI: 10.1128/MCB.22.2.626-634.2002. View

18.

Jarosch E, Taxis C, Volkwein C, Bordallo J, Finley D, Wolf D . Protein dislocation from the ER requires polyubiquitination and the AAA-ATPase Cdc48. Nat Cell Biol. 2002; 4(2):134-9. DOI: 10.1038/ncb746. View

19.

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; 21(4):615-21. PMC: 125867. DOI: 10.1093/emboj/21.4.615. View

20.

Kobayashi T, Tanaka K, Inoue K, Kakizuka A . Functional ATPase activity of p97/valosin-containing protein (VCP) is required for the quality control of endoplasmic reticulum in neuronally differentiated mammalian PC12 cells. J Biol Chem. 2002; 277(49):47358-65. DOI: 10.1074/jbc.M207783200. View