Jentsch, S. & Rumpf, S. Cdc48 (p97): a “molecular gearbox” in the ubiquitin pathway? Trends Biochem. Sci. 32, 6-11

Department of Molecular Cell Biology, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
Trends in Biochemical Sciences (Impact Factor: 11.23). 02/2007; 32(1):6-11. DOI: 10.1016/j.tibs.2006.11.005
Source: PubMed


Cdc48 (p97), a conserved chaperone-like ATPase of eukaryotic cells, has attracted attention recently because of its wide range of cellular functions. Cdc48 is intimately linked to the ubiquitin pathway because its primary action is to segregate ubiquitinated substrates from unmodified partners. This 'segregase' activity is crucial for certain proteasomal degradation pathways and for some nonproteolytic functions of ubiquitin. Cdc48 associates not only with different 'substrate-recruiting cofactors' but also with distinct 'substrate-processing cofactors'. The latter proteins control the degree of ubiquitination of bound substrates by shifting the polyubiquitination reaction into 'forward', 'neutral' or 'reverse'. We discuss how Cdc48 might use this 'gearbox activity' to control protein fate and propose a similar mode of action for the 19S cap of the proteasome.

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    • "Other types of translational difficulties , such as the translation of the polyA sequence that leads to pausing , require another E3 ligase , namely Ltn1 . The ubiquitylated polypeptide requires Cdc48 Ufd1 / Npl4 ( p97 / VCP in mammalians ) , a ubiquitin / ubiquitin - like - modifier - specific segregase ( Jentsch and Rumpf , 2007 ) , to remove it from the ribosome ( Brandman et al . , 2012 ; Defenouillère et al . "
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    ABSTRACT: Proteins are essential components of cellular life, as building blocks, but also to guide and execute all cellular processes. Proteins require a three-dimensional folding, which is constantly being challenged by their environment. Challenges including elevated temperatures or redox changes can alter this fold and result in misfolding of proteins or even aggregation. Cells are equipped with several pathways that can deal with protein stress. Together, these pathways are referred to as the protein quality control network. The network comprises degradation and (re)folding pathways that are intertwined due to the sharing of components and by the overlap in affinity for substrates. Here, we will give examples of this sharing and intertwinement of protein degradation and protein folding and discuss how the fate of a substrate is determined. We will focus on the ubiquitylation of substrates and the role of Hsp70 co-chaperones of the DNAJ class in this process.
    06/2015; 2:35. DOI:10.3389/fmolb.2015.00035
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    • "The monomer is a phylogenetically highly conserved protein that contains two AAA modules, called D1 and D2, that couple coordinated ATP-hydrolysis to conformational changes of the hexameric complex [22]. The ATP-driven conformational changes allow p97 to physically disassemble protein complexes and segregate proteins from their binding partners [23,24]. This “segregase” activity [25,19] is probably limited to ubiquitylated proteins and is essential for a number of cellular pathways, including membrane fusion [26], protein degradation [27,28] and transcription factor maturation through limited degradation [29,25]. "
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    ABSTRACT: Background In mammalian cells, ASPL is involved in insulin-stimulated redistribution of the glucose transporter GLUT4 and assembly of the Golgi apparatus. Its putative yeast orthologue, Ubx4, is important for proteasome localization, endoplasmic reticulum-associated protein degradation (ERAD), and UV-induced degradation of RNA polymerase. Results Here, we show that ASPL is a cofactor of the hexameric ATPase complex, known as p97 or VCP in mammals and Cdc48 in yeast. In addition, ASPL interacts in vitro with NSF, another hexameric ATPase complex. ASPL localizes to the ER membrane. The central area in ASPL, containing both a SHP box and a UBX domain, is required for binding to the p97 N-domain. Knock-down of ASPL does not impair degradation of misfolded secretory proteins via the ERAD pathway. Deletion of UBX4 in yeast causes cycloheximide sensitivity, while ubx4 cdc48-3 double mutations cause proteasome mislocalization. ASPL alleviates these defects, but not the impaired ERAD. Conclusions In conclusion, ASPL and Ubx4 are homologous proteins with only partially overlapping functions. Both interact with p97/Cdc48, but while Ubx4 is important for ERAD, ASPL appears not to share this function.
    BMC Cell Biology 07/2014; 15(1):31. DOI:10.1186/1471-2121-15-31 · 2.34 Impact Factor
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    • "Alternatively, other models suggest that Derlins are involved in unfolding of substrates as well as providing contacts with p97 and its associated factors (Greenblatt et al., 2011). The p97 ATPase binds ubiquitin chain editors that can extend shorter chains as well as deubiquitinating enzymes (DUBs; Jentsch and Rumpf, 2007; Sowa et al., 2009). Two ATPase domains (D1 and D2; Meyer et al., 2012) within p97 form two stacked hexameric rings that provide the energy for protein remodeling and substrate extraction from the membrane or through the retrotranslocon (Hampton and Sommer, 2012). "
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    ABSTRACT: Endoplasmic reticulum (ER)-associated degradation (ERAD) is a universally important process among eukaryotic cells. ERAD is necessary to preserve cell integrity since the accumulation of defective proteins results in diseases associated with neurological dysfunction, cancer, and infections. This process involves recognition of misfolded or misassembled proteins that have been translated in association with ER membranes. Recognition of ERAD substrates leads to their extraction through the ER membrane (retrotranslocation or dislocation), ubiquitination, and destruction by cytosolic proteasomes. This review focuses on ERAD and its components as well as how viruses use this process to promote their replication and to avoid the immune response.
    Frontiers in Microbiology 07/2014; 5:330. DOI:10.3389/fmicb.2014.00330 · 3.99 Impact Factor
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