55 results match your criteria cdc48 cofactors

Seesaw conformations of Npl4 in the human p97 complex and the inhibitory mechanism of a disulfiram derivative.

Nat Commun 2021 01 5;12(1):121. Epub 2021 Jan 5.

Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, 60637, USA.

p97, also known as valosin-containing protein (VCP) or Cdc48, plays a central role in cellular protein homeostasis. Human p97 mutations are associated with several neurodegenerative diseases. Targeting p97 and its cofactors is a strategy for cancer drug development. Read More

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January 2021

The AAA + ATPase valosin-containing protein (VCP)/p97/Cdc48 interaction network in Leishmania.

Sci Rep 2020 08 4;10(1):13135. Epub 2020 Aug 4.

Division of Infectious Disease and Immunity, CHU de Quebec Research Center-Laval University, 2705 Laurier Blvd, Quebec, QC, G1V 4G2, Canada.

Valosin-containing protein (VCP)/p97/Cdc48 is an AAA + ATPase associated with many ubiquitin-dependent cellular pathways that are central to protein quality control. VCP binds various cofactors, which determine pathway selectivity and substrate processing. Here, we used co-immunoprecipitation and mass spectrometry studies coupled to in silico analyses to identify the Leishmania infantum VCP (LiVCP) interactome and to predict molecular interactions between LiVCP and its major cofactors. Read More

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Structure of the PUB Domain from Ubiquitin Regulatory X Domain Protein 1 (UBXD1) and Its Interaction with the p97 AAA+ ATPase.

Biomolecules 2019 12 14;9(12). Epub 2019 Dec 14.

University of Duisburg-Essen, Structural and Medicinal Biochemistry, Centre for Medical Biotechnology (ZMB), 45117 Essen, Germany.

AAA+ ATPase p97/valosin-containing protein (VCP)/Cdc48 is a key player in various cellular stress responses in which it unfolds ubiquitinated proteins to facilitate their degradation by the proteasome. P97 works in different cellular processes using alternative sets of cofactors and is implicated in multiple degenerative diseases. Ubiquitin regulatory X domain protein 1 (UBXD1) has been linked to pathogenesis and is unique amongst p97 cofactors because it interacts with both termini of p97. Read More

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December 2019

Common Mode of Remodeling AAA ATPases p97/CDC48 by Their Disassembling Cofactors ASPL/PUX1.

Structure 2019 12 21;27(12):1830-1841.e3. Epub 2019 Oct 21.

Max-Delbrück-Centrum für Molekulare Medizin, 13125 Berlin, Germany; Institut für Chemie und Biochemie, Freie Universität Berlin, 14195 Berlin, Germany. Electronic address:

The hexameric ring structure of the type II AAA+ ATPases is considered as stable and permanent. Recently, the UBX domain-containing cofactors Arabidopsis thaliana PUX1 and human alveolar soft part sarcoma locus (ASPL) were reported to bind and disassemble the cognate AAA+ ATPases AtCDC48 and human p97. Here, we present two crystal structures related to these complexes: a truncated AtCDC48 (AtCDC48-ND1) and a hybrid complex containing human p97-ND1 and the UBX domain of plant PUX1 (p97-ND1:PUX1-UBX). Read More

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December 2019

Insights into the Design of p97-targeting Small Molecules from Structural Studies on p97 Functional Mechanism.

Curr Med Chem 2020 ;27(2):298-316

School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui 230009, China.

p97, also known as valosin-containing protein or CDC48, is a member of the AAA+ protein family that is highly conserved in eukaryotes. It binds to various cofactors in the body to perform its protein-unfolding function and participates in DNA repair, degradation of subcellular membrane proteins, and protein quality control pathways, among other processes. Its malfunction can lead to many diseases, such as inclusion body myopathy, associated with Paget's disease of bone and/or frontotemporal dementia, amyotrophic lateral sclerosis disease, and others. Read More

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February 2020

In Vitro Reconstitution Defines the Minimal Requirements for Cdc48-Dependent Disassembly of the CMG Helicase in Budding Yeast.

Cell Rep 2019 Sep;28(11):2777-2783.e4

The MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, Scotland DD1 5EH, UK. Electronic address:

Disassembly of the replisome is the final step of chromosome duplication in eukaryotes. In budding yeast and metazoa, cullin ubiquitin ligases are required to ubiquitylate the Cdc45-MCM-GINS (CMG) helicase that lies at the heart of the replisome, leading to a disassembly reaction that is dependent upon the ATPase known as Cdc48 or p97. Here, we describe the reconstitution of replisome disassembly, using a purified complex of the budding yeast replisome in association with the cullin ligase SCF. Read More

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September 2019

Structure of the Cdc48 ATPase with its ubiquitin-binding cofactor Ufd1-Npl4.

Nat Struct Mol Biol 2018 07 2;25(7):616-622. Epub 2018 Jul 2.

Howard Hughes Medical Institute and Department of Cell Biology, Harvard Medical School, Boston, MA, USA.

Many polyubiquitinated proteins are extracted from membranes or complexes by the conserved ATPase Cdc48 (in yeast; p97 or VCP in mammals) before proteasomal degradation. Each Cdc48 hexamer contains two stacked ATPase rings (D1 and D2) and six N-terminal (N) domains. Cdc48 binds various cofactors, including the Ufd1-Npl4 heterodimer. Read More

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Cdc48/p97 segregase is modulated by cyclin-dependent kinase to determine cyclin fate during G1 progression.

EMBO J 2018 08 27;37(16). Epub 2018 Jun 27.

Molecular Biology Institute of Barcelona IBMB-CSIC, Barcelona, Catalonia, Spain

Cells sense myriad signals during G1, and a rapid response to prevent cell cycle entry is of crucial importance for proper development and adaptation. Cln3, the most upstream G1 cyclin in budding yeast, is an extremely short-lived protein subject to ubiquitination and proteasomal degradation. On the other hand, nuclear accumulation of Cln3 depends on chaperones that are also important for its degradation. Read More

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Two Cdc48 cofactors Ubp3 and Ubx2 regulate mitochondrial morphology and protein turnover.

J Biochem 2018 Nov;164(5):349-358

Department of Molecular Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo 2-2-1, Chuo-ku, Kumamoto, Japan.

Mitochondria continuously undergo coordinated fusion and fission during vegetative growth to keep their homogeneity and to remove damaged components. A cytosolic AAA ATPase, Cdc48, is implicated in the mitochondrial fusion event and turnover of a fusion-responsible GTPase in the mitochondrial outer membrane, Fzo1, suggesting a possible linkage of mitochondrial fusion and Fzo1 turnover. Here, we identified two Cdc48 cofactor proteins, Ubp3 and Ubx2, involving mitochondria regulation. Read More

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November 2018

Toward an understanding of the Cdc48/p97 ATPase.

F1000Res 2017 3;6:1318. Epub 2017 Aug 3.

Howard Hughes Medical Institute and Department of Cell Biology, Harvard Medical School, Boston, MA, USA.

A conserved AAA+ ATPase, called Cdc48 in yeast and p97 or VCP in metazoans, plays an essential role in many cellular processes by segregating polyubiquitinated proteins from complexes or membranes. For example, in endoplasmic reticulum (ER)-associated protein degradation (ERAD), Cdc48/p97 pulls polyubiquitinated, misfolded proteins out of the ER and transfers them to the proteasome. Cdc48/p97 consists of an N-terminal domain and two ATPase domains (D1 and D2). Read More

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A Mighty "Protein Extractor" of the Cell: Structure and Function of the p97/CDC48 ATPase.

Front Mol Biosci 2017 13;4:39. Epub 2017 Jun 13.

Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of HealthBethesda, MD, United States.

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. Read More

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Molecular Mechanism of Substrate Processing by the Cdc48 ATPase Complex.

Cell 2017 05;169(4):722-735.e9

Howard Hughes Medical Institute and Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA. Electronic address:

The Cdc48 ATPase and its cofactors Ufd1/Npl4 (UN) extract polyubiquitinated proteins from membranes or macromolecular complexes, but how they perform these functions is unclear. Cdc48 consists of an N-terminal domain that binds UN and two stacked hexameric ATPase rings (D1 and D2) surrounding a central pore. Here, we use purified components to elucidate how the Cdc48 complex processes substrates. Read More

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The Interplay of Cofactor Interactions and Post-translational Modifications in the Regulation of the AAA+ ATPase p97.

Front Mol Biosci 2017 13;4:21. Epub 2017 Apr 13.

Rudolf Virchow Center for Experimental Biomedicine, University of WürzburgWürzburg, Germany.

The hexameric type II AAA ATPase (ATPase associated with various activities) p97 (also referred to as VCP, Cdc48, and Ter94) is critically involved in a variety of cellular activities including pathways such as DNA replication and repair which both involve chromatin remodeling, and is a key player in various protein quality control pathways mediated by the ubiquitin proteasome system as well as autophagy. Correspondingly, p97 has been linked to various pathophysiological states including cancer, neurodegeneration, and premature aging. p97 encompasses an N-terminal domain, two highly conserved ATPase domains and an unstructured C-terminal tail. Read More

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CUL-2 and UBXN-3 drive replisome disassembly during DNA replication termination and mitosis.

Nat Cell Biol 2017 May 3;19(5):468-479. Epub 2017 Apr 3.

MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.

Replisome disassembly is the final step of DNA replication in eukaryotes, involving the ubiquitylation and CDC48-dependent dissolution of the CMG helicase (CDC45-MCM-GINS). Using Caenorhabditis elegans early embryos and Xenopus laevis egg extracts, we show that the E3 ligase CUL-2 associates with the replisome and drives ubiquitylation and disassembly of CMG, together with the CDC-48 cofactors UFD-1 and NPL-4. Removal of CMG from chromatin in frog egg extracts requires CUL2 neddylation, and our data identify chromatin recruitment of CUL2 as a key regulated step during DNA replication termination. Read More

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Structure and functions of the chaperone-like p97/CDC48 in plants.

Biochim Biophys Acta Gen Subj 2017 Jan 4;1861(1 Pt A):3053-3060. Epub 2016 Oct 4.

Agroécologie, AgroSup Dijon, CNRS, INRA, Univ. Bourgogne Franche-Comté, F-21000 Dijon, France. Electronic address:

Background: The chaperone-like p97 is a member of the AAA+ ATPase enzyme family that contributes to numerous cellular activities. P97 has been broadly studied in mammals (VCP/p97) and yeasts (CDC48: Cell Division Cycle 48/p97) and numerous investigations highlighted that this protein is post-translationally regulated, is structured in homohexamer and interacts with partners and cofactors that direct it to distinct cellular signalization pathway including protein quality control and degradation, cell cycle regulation, genome stability, vesicular trafficking, autophagy and immunity.

Scope Of Review: p97 is also conserved in plants (CDC48) but its functions are less understood. Read More

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January 2017

Cardiac-Restricted Expression of VCP/TER94 RNAi or Disease Alleles Perturbs Heart Structure and Impairs Function.

J Cardiovasc Dev Dis 2016 Jun 24;3(2). Epub 2016 May 24.

Division of Cardiology, Department of Medicine, Johns Hopkins University, Ross 1050, 720 Rutland Avenue, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University, Ross 1050, 720 Rutland Avenue, Baltimore, MD 21205, USA.

Valosin-containing protein (VCP) is a highly conserved mechanoenzyme that helps maintain protein homeostasis in all cells and serves specialized functions in distinct cell types. In skeletal muscle, it is critical for myofibrillogenesis and atrophy. However, little is known about VCP's role(s) in the heart. Read More

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Strategic role of the ubiquitin-dependent segregase p97 (VCP or Cdc48) in DNA replication.

Chromosoma 2017 02 18;126(1):17-32. Epub 2016 Apr 18.

Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Roosevelt Drive, Oxford, OX3 7DQ, UK.

Genome amplification (DNA synthesis) is one of the most demanding cellular processes in all proliferative cells. The DNA replication machinery (also known as the replisome) orchestrates genome amplification during S-phase of the cell cycle. Genetic material is particularly vulnerable to various events that can challenge the replisome during its assembly, activation (firing), progression (elongation) and disassembly from chromatin (termination). Read More

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February 2017

Doa1 targets ubiquitinated substrates for mitochondria-associated degradation.

J Cell Biol 2016 Apr 4;213(1):49-63. Epub 2016 Apr 4.

National Institute of Biological Sciences, Beijing 102206, China

Mitochondria-associated degradation (MAD) mediated by the Cdc48 complex and proteasome degrades ubiquitinated mitochondrial outer-membrane proteins. MAD is critical for mitochondrial proteostasis, but it remains poorly characterized. We identified several mitochondrial Cdc48 substrates and developed a genetic screen assay to uncover regulators of the Cdc48-dependent MAD pathway. Read More

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Structure and function of the AAA+ ATPase p97/Cdc48p.

Gene 2016 May 3;583(1):64-77. Epub 2016 Mar 3.

Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, United States. Electronic address:

p97 (also known as valosin-containing protein (VCP) in mammals or Cdc48p in Saccharomyces cerevisiae) is an evolutionarily conserved ATPase present in all eukaryotes and archaebacteria. In conjunction with a collection of cofactors and adaptors, p97/Cdc48p performs an array of biological functions mostly through modulating the stability of 'client' proteins. Using energy from ATP hydrolysis, p97/Cdc48p segregates these molecules from immobile cellular structures such as protein assemblies, membrane organelles, and chromatin. Read More

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Control of p97 function by cofactor binding.

FEBS Lett 2015 Sep 29;589(19 Pt A):2578-89. Epub 2015 Aug 29.

Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany. Electronic address:

p97 (also known as Cdc48, Ter94, and VCP) is an essential, abundant and highly conserved ATPase driving the turnover of ubiquitylated proteins in eukaryotes. Even though p97 is involved in highly diverse cellular pathways and processes, it exhibits hardly any substrate specificity on its own. Instead, it relies on a large number of regulatory cofactors controlling substrate specificity and turnover. Read More

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September 2015

The ubiquitin-selective chaperone Cdc48/p97 associates with Ubx3 to modulate monoubiquitylation of histone H2B.

Nucleic Acids Res 2014 2;42(17):10975-86. Epub 2014 Sep 2.

Sorbonne Paris Cité, INSERM UMR944, CNRS UMR7212, Equipe labellisée Ligue contre le cancer, University of Paris Diderot, Hôpital St. Louis 1, Avenue Claude Vellefaux 75475 Paris Cedex 10, France

Cdc48/p97 is an evolutionary conserved ubiquitin-dependent chaperone involved in a broad array of cellular functions due to its ability to associate with multiple cofactors. Aside from its role in removing RNA polymerase II from chromatin after DNA damage, little is known about how this AAA-ATPase is involved in the transcriptional process. Here, we show that yeast Cdc48 is recruited to chromatin in a transcription-coupled manner and modulates gene expression. Read More

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February 2015

The VCP/p97 system at a glance: connecting cellular function to disease pathogenesis.

J Cell Sci 2014 Sep 21;127(Pt 18):3877-83. Epub 2014 Aug 21.

Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO 63110, USA

The ATPase valosin-containing protein (VCP)/p97 has emerged as a central and important element of the ubiquitin system. Together with a network of cofactors, it regulates an ever-expanding range of processes that stretch into almost every aspect of cellular physiology. Its main role in proteostasis and key functions in signaling pathways are of relevance to degenerative diseases and genomic stability. Read More

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September 2014

Emerging mechanistic insights into AAA complexes regulating proteasomal degradation.

Biomolecules 2014 Aug 6;4(3):774-94. Epub 2014 Aug 6.

Department of Molecular Structural Biology, Max-Planck Institute of Biochemistry, Martinsried D-82152, Germany.

The 26S proteasome is an integral element of the ubiquitin-proteasome system(UPS) and, as such, responsible for regulated degradation of proteins in eukaryotic cells.It consists of the core particle, which catalyzes the proteolysis of substrates into small peptides, and the regulatory particle, which ensures specificity for a broad range of substrates.The heart of the regulatory particle is an AAA-ATPase unfoldase, which is surrounded by non-ATPase subunits enabling substrate recognition and processing. Read More

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Ubiquitin signals proteolysis-independent stripping of transcription factors.

Mol Cell 2014 Mar 6;53(6):893-903. Epub 2014 Mar 6.

Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523, USA. Electronic address:

Ubiquitination of transcription activators has been reported to regulate transcription via both proteolytic and nonproteolytic routes, yet the function of the ubiquitin (Ub) signal in the nonproteolytic process is poorly understood. By use of the heterologous transcription activator LexA-VP16 in Saccharomyces cerevisiae, we show that monoubiquitin fusion of the activator prevents stable interactions between the activator and DNA, leading to transcription inhibition without activator degradation. We identify the AAA(+) ATPase Cdc48 and its cofactors as the Ub receptor responsible for extracting the monoubiquitinated activator from DNA. Read More

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The Cdc48-Vms1 complex maintains 26S proteasome architecture.

Biochem J 2014 Mar;458(3):459-67

*Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, U.S.A.

The 26S proteasome is responsible for most regulated protein turnover and for the degradation of aberrant proteins in eukaryotes. The assembly of this ~2.5 MDa multicatalytic protease requires several dedicated chaperones and, once assembled, substrate selectivity is mediated by ubiquitin conjugation. Read More

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Cdc48: a swiss army knife of cell biology.

J Amino Acids 2013 15;2013:183421. Epub 2013 Sep 15.

Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX 78229, USA.

Cdc48 (also called VCP and p97) is an abundant protein that plays essential regulatory functions in a broad array of cellular processes. Working with various cofactors, Cdc48 utilizes its ATPase activity to promote the assembly and disassembly of protein complexes. Here, we review key biological functions and regulation of Cdc48 in ubiquitin-related events. Read More

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Identification and characterization of a gene encoding a UBX domain-containing protein in the migratory locust, Locusta migratoria manilensis.

Insect Sci 2013 Aug 23;20(4):497-504. Epub 2012 Oct 23.

Institute of Entomology and Molecular Biology, Chongqing Key Laboratory of Animal Biology, College of Life Sciences, Chongqing Normal University, Chongqing, China.

Ubiquitin regulatory X (UBX) domain-containing proteins are believed to function as cofactors for p97/CDC48, an adenosine triphosphatase shown to be involved in multiple cellular processes. In the present study, a full-length complementary DNA (cDNA) of UBX domain-containing gene, termed LmUBX1, was cloned from Locusta migratoria manilensis and characterized, using random amplification of cDNA ends polymerase chain reaction (RACE PCR), sequence analysis and quantitative real-time PCR. LmUBX1, 1 600 bp in length, is predicted to encode a 446-amino acid protein with a predicted molecular weight of 51. Read More

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The budding yeast Cdc48(Shp1) complex promotes cell cycle progression by positive regulation of protein phosphatase 1 (Glc7).

PLoS One 2013 13;8(2):e56486. Epub 2013 Feb 13.

Department of Biochemistry, Biocenter, University of Würzburg, Würzburg, Germany.

The conserved, ubiquitin-selective AAA ATPase Cdc48 regulates numerous cellular processes including protein quality control, DNA repair and the cell cycle. Cdc48 function is tightly controlled by a multitude of cofactors mediating substrate specificity and processing. The UBX domain protein Shp1 is a bona fide substrate-recruiting cofactor of Cdc48 in the budding yeast S. Read More

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A ribosome-bound quality control complex triggers degradation of nascent peptides and signals translation stress.

Cell 2012 Nov;151(5):1042-54

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.

The conserved transcriptional regulator heat shock factor 1 (Hsf1) is a key sensor of proteotoxic and other stress in the eukaryotic cytosol. We surveyed Hsf1 activity in a genome-wide loss-of-function library in Saccaromyces cerevisiae as well as ~78,000 double mutants and found Hsf1 activity to be modulated by highly diverse stresses. These included disruption of a ribosome-bound complex we named the Ribosome Quality Control Complex (RQC) comprising the Ltn1 E3 ubiquitin ligase, two highly conserved but poorly characterized proteins (Tae2 and Rqc1), and Cdc48 and its cofactors. Read More

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November 2012

The Cdc48 protein and its cofactor Vms1 are involved in Cdc13 protein degradation.

J Biol Chem 2012 Aug 20;287(32):26788-95. Epub 2012 Jun 20.

Institute of Biotechnology, Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas 78245, USA.

Vms1 is a newly identified Cdc48-binding protein. The biological function of Vms1 remains obscure. Here, we show that both Cdc48 and Vms1, but not Cdc48 cofactors Ufd1 and Ufd2, are crucial for the degradation of Cdc13, a telomere regulator. Read More

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