Abstract
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. This enzyme hydrolyzes ATP and utilizes the resulting energy to extract or disassemble protein targets modified with ubiquitin from stable protein assemblies, chromatin and membranes. p97 participates in highly diverse cellular processes and hence its activity is tightly controlled. This is achieved by multiple regulatory cofactors, which either associate with the N-terminal domain or interact with the extreme C-terminus via distinct binding elements and target p97 to specific cellular pathways, sometimes requiring the simultaneous association with more than one cofactor. Most cofactors are recruited to p97 through conserved binding motifs/domains and assist in substrate recognition or processing by providing additional molecular properties. A tight control of p97 cofactor specificity and diversity as well as the assembly of higher-order p97-cofactor complexes is accomplished by various regulatory mechanisms, which include bipartite binding, binding site competition, changes in oligomeric assemblies, and nucleotide-induced conformational changes. Furthermore, post-translational modifications (PTMs) like acetylation, palmitoylation, phosphorylation, SUMOylation, and ubiquitylation of p97 have been reported which further modulate its diverse molecular activities. In this review, we will describe the molecular basis of p97-cofactor specificity/diversity and will discuss how PTMs can modulate p97-cofactor interactions and affect the physiological and patho-physiological functions of p97.
Highlights
P97 belongs to the functionally highly diverse AAA+ (ATPase associated with various cellular activities) superfamily of proteins, which is characterized by conserved ATPase core domains
In all these processes p97 extracts or disassembles ubquitylated substrates from membranes, chromatin or, in general, from large protein complexes often, but not always, resulting in downstream degradation by the proteasome (Figure 1B): (i) p97 has been shown to extract different ubiquitylated proteins from chromatin in processes such as cell cycle regulation, transcriptional and replication stress responses, several DNA repair processes, or replication. These proteins are either degraded by the proteasome or recycled to modulate the dynamics of chromatin regulators; (ii) p97 is involved in various membrane trafficking processes, including Golgi reassembly at the end of mitosis and in endocytosis; (iii) p97 is a key player in multiple protein quality control pathways mediated by the ubiquitin proteasome system and autophagy
It is involved in the extraction of misfolded proteins from the ER (ER-associated degradation, ERAD; reviewed in Stolz et al, 2011; Wolf and Stolz, 2012) and translocates damaged mitochondrial proteins into the cytosol in a process called outer mitochondrial membrane associated degradation (OMMAD; Heo et al, 2010; Xu et al, 2011; Hemion et al, 2014); p97 is part of the ribosome-quality control complex (RQC), which is involved in the degradation of stalled nascent peptides
Summary
P97 ( known as VCP, Cdc, and Ter94) belongs to the functionally highly diverse AAA+ (ATPase associated with various cellular activities) superfamily of proteins, which is characterized by conserved ATPase core domains. Upon ATP-binding and hydrolysis significant conformational changes occur, which are transmitted via long flexible linkers from the D2 domain to the D1 domain and further to the N domain (Figure 1D)(Banerjee et al, 2016; Na and Song, 2016; Schuller et al, 2016; reviewed in Xia et al, 2016) These conformational changes, which are regulated by intradomain (within the same protomer; Ye et al, 2003; Chou et al, 2014) and interdomain (between adjacent protomers; Huang et al, 2012; Li et al, 2012; Hänzelmann and Schindelin, 2016b) signaling mechanisms include: (i) Opening and closing of the D2 pore; (ii) Rotational movement of the ATPase rings; (ii) Up and down movements of the N domain. We will focus on the molecular basis of p97cofactor specificity/diversity and will discuss how PTMs can modulate p97-cofactor interactions and affect the physiological and patho-physiological functions of p97
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