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. Given the broad employment of Cdc48 in cell biology and its intimate ties to human diseases (e.g., amyotrophic lateral sclerosis), studies of Cdc48 will bring significant insights into the mechanism and function of ubiquitin in health and diseases. 1. Introduction Thirty years ago when David Botstein’s laboratory first isolated cdc48-1 allele among 18 cold-sensitive yeast mutants defective in cell cycle progression [1], little did they know how much power is embedded in CDC48. Although Cdc48 was initially suspected to play a pivotal role in some nuclear event(s) essential for cell cycle progression, it is now known to be a key regulator for a myriad of cellular processes in nucleus, cytosol, mitochondria, peroxisome, endoplasmic reticulum (ER), Golgi, lysosome, and plasma membrane [2–6]. Befittingly, Cdc48 is one of the most abundant proteins in eukaryotic cells, accounting for 1% of cytosolic proteins [5, 7]. The mammalian homologue of Cdc48 is also called p97 for molecular weight or VCP (valosin-containing protein) by the groups that identified it with different approaches in various systems [1, 8, 9]. Although little attention was paid to Cdc48 early on, its stock has risen dramatically in recent years (Figure 1). Figure 1: Number of papers on Cdc48 published since 1982. Key words “Cdc48, VCP, and p97” were used to search PUBMED for papers on Cdc48 from 1982 to 2012. Evolutionally conserved Cdc48 is an ATPase essential for cell growth and survival. It is a central component in many ubiquitin-mediated pathways and participates in a wide range of biological events, including cell cycle regulation, protein degradation, membrane fusion, DNA replication, gene expression, DNA damage response, apoptosis, and autophagy [2–5, 7, 10, 11]. A book would be needed to comprehensively cover the various functions of Cdc48. Here, we specifically highlight a few key aspects of Cdc48: the biochemical properties, physiological regulation, and crucial biological functions. 2. Biochemical Properties 2.1. ATPase Activity The biochemical basis for broad utility of Cdc48 in cell biology lies in its ATPase activity. ATPase function was first demonstrated with p97, Xenopus homologue of Cdc48 [9], and subsequently shown to
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