Yeast cell cycle protein CDC48p shows full-length homology to the mammalian protein VCP and is a member of a protein family involved in secretion, peroxisome formation, and gene expression.

Fröhlich, Kai‐Uwe; Fries, Hans-Werner; Rüdiger, Manfred; Erdmann, Ralf; Botstein, David; Mecke, Dieter

doi:10.1083/jcb.114.3.443

Cited by 289 publications

(177 citation statements)

References 62 publications

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“…The apparent diversity of cellular roles of this group of AAA proteins initially made it difficult to define a common functional feature that characterizes this group. The CDC48 proteins were first identified in yeast as cell cycle control mutants (Frohlich et al 1991), while the Sec proteins were deficient in cellular secretion processes (Novick et al 1980). Pas proteins are implicated in the proliferation of peroxisomes during growth (Kunau et al 1993).…”

Section: The Membrane Fusion Proteinsmentioning

confidence: 99%

“…AAA proteins were first isolated around 1990 (Peters et al 1990;Frohlich et al 1991) with the identification of several eukaryotic proteins that contained what was later termed the CAD. To date, more than 100 CADcontaining AAA proteins have been isolated, with examples from each biological urkingdom-eukaryotes, eubacteria and archaebacteria (Woese, Kandler, and Wheelis 1990).…”

Section: Introductionmentioning

confidence: 99%

“…Although the domain contains a Walker Type I ATPase motif that is essential for protein function, the CAD is clearly different from other ATPase protein families such as DEAD-box helicases (Hodgman 1992), ion pumps, and ABC transporters (Fath and Kolter 1993). Members of the CADcontaining AAA family have been shown to participate in vesicle fusion (Sollner et al 1993), peroxisomal protein import (Heyman et al 1994), mitochondrial membrane-bound proteolysis (Guelin et al 1994;Tomoyasu et al 1995), cell cycle control (Frohlich et al 1991), proteasomal regulation Dubiel et al 1995), mitotic spindle formation (Clark-Maquire and Mains 1994), signal transduction (Schulte et al 1994), protein complex formation (Nobrega et al 1992; Paul and Tzagoloff 1995) and possibly transcription (Swaffield et al 1995;Lee et al 1995;Xu et al 1995). Considering different facets of each known biological activity attributed to AAA proteins, Confalonieri and Duguet (1995) have proposed two unifying functions for CADs: (1) an ATP-dependent proteasomal or chaperone function and (2) an ability to act as an ATP-depending anchorage, or ''protein clamp.…”

Section: Introductionmentioning

confidence: 99%

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The Evolution of the Conserved ATPase Domain (CAD): Reconstructing the History of an Ancient Protein Module

Swaffield

Purugganan

1997

J Mol Evol

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Abstract. The AAA proteins (ATPases Associated with a variety of cellular Activities) are found in eubacterial, archaebacterial, and eukaryotic species and participate in a large number of cellular processes, including protein degradation, vesicle fusion, cell cycle control, and cellular secretory processes. The AAA proteins are characterized by the presence of a 230 to 250-amino acid ATPase domain referred to as the Conserved ATPase Domain or CAD. Phylogenetic analysis of 133 CAD sequences from 38 species reveal that AAA CADs are organized into discrete groups that are related not only in structure but in cellular function. Evolutionary analyses also indicate that the CAD was present in the last common ancestor of eubacteria, archaebacteria, and eukaryotes. The eubacterial CADs are found in metalloproteases, while CAD-containing proteins in the archaebacterial and eukaryotic lineages appear to have diversified by a series of gene duplication events that lead to the establishment of different functional AAA proteins, including proteasomal regulatory, NSF/Sec, and Pas proteins. The phylogeny of the CADs provides the basis for establishing the patterns of evolutionary change that characterize the AAA proteins.

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Section: The Membrane Fusion Proteinsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Evolution of the Conserved ATPase Domain (CAD): Reconstructing the History of an Ancient Protein Module

Swaffield

Purugganan

1997

J Mol Evol

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“…For one, conditional mutants in Cdc48p do not have a secretion defect. Cdc48 mutants are unable to divide their nuclei during cell division and unable to fuse their nuclei during karyogamy (Moir et al, 1982;Frö hlich et al, 1991;Latterich et al, 1995). Despite the fact that ER membranes from cdc48 mutant yeast are defective in fusion in vitro (Latterich et al, 1995), the peripheral ER in such cells behaves normally (and dynamically) in vivo, even at temperatures nonpermissive for Cdc48p function (Prinz et al, 2000).…”

Section: Nsf and Membrane Fusionmentioning

confidence: 99%

Distinct Roles for the AAA ATPases NSF and p97 in the Secretory Pathway

Dalal

Rosser

Cyr

et al. 2004

MBoC

166

176

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NSF and p97 are related AAA proteins implicated in membrane trafficking and organelle biogenesis. p97 is also involved in pathways that lead to ubiquitin-dependent proteolysis, including ER-associated degradation (ERAD). In this study, we have used dominant interfering ATP-hydrolysis deficient mutants (NSF(E329Q) and p97(E578Q)) to compare the function of these AAA proteins in the secretory pathway of mammalian cells. Expressing NSF(E329Q) promotes disassembly of Golgi stacks into dispersed vesicular structures. It also rapidly inhibits glycosaminoglycan sulfation, reflecting disruption of intra-Golgi transport. In contrast, expressing p97(E578Q) does not affect Golgi structure or function; glycosaminoglycans are normally sulfated and secreted, as is the VSV-G ts045 protein. Instead, expression of p97(E578Q) causes ubiquitinated proteins to accumulate on ER membranes and slows degradation of the ERAD substrate cystic-fibrosis transmembrane-conductance regulator. In addition, expression of p97(E578Q) eventually causes the ER to swell. More specific assessment of effects of p97(E578Q) on organelle assembly shows that the Golgi apparatus disperses and reassembles normally after treatment with brefeldin A and during mitosis. These findings demonstrate that ATPhydrolysis-dependent activities of NSF and p97 in the cell are not equivalent and suggest that only NSF is directly involved in regulating membrane fusion. INTRODUCTIONMembrane fusion is an essential step in all forms of vesicle trafficking and organelle assembly. Fusion is driven by a series of regulated protein-protein interactions. Many participating proteins have been identified, and their specific roles are gradually coming to light (reviewed in Jahn et al., 2003). Among these proteins are a number of ATPases.N-ethyl maleimide sensitive factor (NSF) was one of the first proteins specifically linked to membrane fusion (Wilson et al., 1989). It belongs to a family of chaperone-like ATPases known as AAA (ATPases associated with a variety of cellular activities) proteins (Neuwald et al., 1999). NSF together with ␣-SNAP (soluble NSF attachment protein) dissociates the SNARE (SNAP receptor) complexes that promote association and fusion of cellular membranes. More recently, NSF has also been implicated in other cellular processes on the basis of its ability to bind the AMPA receptor GluR2, ␤-arrestin 1, and GATE-16 (reviewed in Whiteheart et al., 2001). However, its role in SNARE disassembly and membrane fusion remains its best understood function.Not all ATP-requiring steps that lead to membrane fusion can be attributed to NSF (Goda and Pfeffer, 1991;Latterich and Schekman, 1994;Rodriguez et al., 1994;Wilson, 1995).Other ATPases must therefore be involved. One AAA protein thought to be an alternate to NSF is known as p97 (also referred to as valosin-containing protein, VCP). p97 is an abundant and highly conserved protein (Peters et al., 1990) whose cellular function has been the subject of much debate. A break in the mystery of p97's function came when it turn...

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“…Early observations in yeast and recent findings using Xenopus egg extracts suggested that Cdc48/p97 regulates spindle disassembly during exit from mitosis (6,7). For example, spindle regulators such as the Polo-like kinase Plx remain attached and probably stabilize the spindle in the absence of p97 Ufd1/Npl4 .…”

mentioning

confidence: 99%

Cell cycle progression requires the CDC-48 ^{UFD−1/NPL−4} complex for efficient DNA replication

Mouysset

Deichsel

Moser

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Since cdc48 mutants were isolated by the first genetic screens for cell division cycle (cdc) mutants in yeast, the requirement of the chaperone-like ATPase Cdc48/p97 during cell division has remained unclear. Here, we discover an unanticipated function for Caenorhabditis elegans CDC-48 in DNA replication linked to cell cycle control. Our analysis of the CDC-48 UFD؊1/NPL؊4 complex identified a general role in S phase progression of mitotic cells essential for embryonic cell division and germline development of adult worms. These developmental defects result from activation of the DNA replication checkpoint caused by replication stress. Similar to loss of replication licensing factors, DNA content is strongly reduced in worms depleted for CDC-48, UFD-1, and NPL-4. In addition, these worms show decreased DNA synthesis and hypersensitivity toward replication blocking agents. Our findings identified a role for CDC-48 UFD؊1/NPL؊4 in DNA replication, which is important for cell cycle progression and genome stability.ATL-1/ATR ͉ C. elegans ͉ CDC-48/p97 ͉ genome stability M any biological processes including development and cell division are tightly controlled by ubiquitin-mediated protein degradation. A central factor for mobilizing and targeting ubiquitylated substrates to the 26S proteasome is Cdc48/p97 (Cdc48 in yeast, CDC-48 in C. elegans, p97 in mammals), a chaperone-like AAA ATPase (1). Its activity is modulated by alternative adaptor proteins, which determine recruitment and processing of specific substrates. Cdc48/p97 forms a complex with the cofactors Ufd1 and Npl4 that is involved in endoplasmic reticulum (ER)-associated protein degradation (ERAD) (2), membrane fusion and cell cycle progression (3, 4). Temperature sensitive cdc48 mutants have already been isolated by early cdc-screens (5) in Saccharomyces cerevisiae. However, the essential role of Cdc48 during cell cycle progression remained elusive.Meanwhile, different activities of Cdc48/p97 in mitosis have been addressed by several studies. Early observations in yeast and recent findings using Xenopus egg extracts suggested that Cdc48/p97 regulates spindle disassembly during exit from mitosis (6, 7). For example, spindle regulators such as the Polo-like kinase Plx remain attached and probably stabilize the spindle in the absence of p97 Ufd1/Npl4 . However, contradictory evidence exists concerning a specific role of the p97 Ufd1/Npl4 complex in spindle dynamics (8,9). Beside spindle function, p97 together with its Ufd1-Npl4 cofactor is important for nuclear envelope assembly (10). Interestingly, it has been shown that p97 stimulates nucleus reformation after mitosis by extracting and thereby inactivating the mitotic progression kinase Aurora B from chromatin (11). Together, these diverse processes involving Cdc48/p97 suggest the existence of multiple substrates that need to be regulated during mitosis.Recently, we found that the C. elegans Cdc48/p97 homologues CDC-48.1 and CDC-48.2 form an evolutionarily conserved complex with UFD-1 and NPL-4 important for t...

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Yeast cell cycle protein CDC48p shows full-length homology to the mammalian protein VCP and is a member of a protein family involved in secretion, peroxisome formation, and gene expression.

Cited by 289 publications

References 62 publications

The Evolution of the Conserved ATPase Domain (CAD): Reconstructing the History of an Ancient Protein Module

The Evolution of the Conserved ATPase Domain (CAD): Reconstructing the History of an Ancient Protein Module

Distinct Roles for the AAA ATPases NSF and p97 in the Secretory Pathway

Cell cycle progression requires the CDC-48 ^{UFD−1/NPL−4} complex for efficient DNA replication

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Yeast cell cycle protein CDC48p shows full-length homology to the mammalian protein VCP and is a member of a protein family involved in secretion, peroxisome formation, and gene expression.

Cited by 289 publications

References 62 publications

The Evolution of the Conserved ATPase Domain (CAD): Reconstructing the History of an Ancient Protein Module

The Evolution of the Conserved ATPase Domain (CAD): Reconstructing the History of an Ancient Protein Module

Distinct Roles for the AAA ATPases NSF and p97 in the Secretory Pathway

Cell cycle progression requires the CDC-48 UFD−1/NPL−4 complex for efficient DNA replication

Contact Info

Product

Resources

About

Cell cycle progression requires the CDC-48 ^{UFD−1/NPL−4} complex for efficient DNA replication