Abstract
The separation of sister chromatids at anaphase, which is regulated by an E3 ubiquitin ligase called the anaphase-promoting complex/cyclosome (APC/C), is arguably the most important irrevocable event during the cell cycle. The APC/C and cyclin-dependent kinase 1 (Cdk1) are just two of the many significant cell cycle regulators and exert control through ubiquitylation and phosphorylation, respectively. The temporal and spatial regulation of the APC/C is achieved by multiple mechanisms, including phosphorylation, interaction with the structurally related co-activators Cdc20 and Cdh1, loading of distinct E2 ubiquitin-conjugating enzymes, binding with inhibitors and differential affinities for various substrates. Since the discovery of APC/C 25 years ago, intensive studies have uncovered many aspects of APC/C regulation, but we are still far from a full understanding of this important cellular machinery. Recent high-resolution cryogenic electron microscopy analysis and reconstitution of the APC/C have greatly advanced our understanding of molecular mechanisms underpinning the enzymatic properties of APC/C. In this review, we will examine the historical background and current understanding of APC/C regulation.
Highlights
The ubiquitin pathway is an ATP-dependent tagging system which regulates a plethora of events in eukaryotic cells by controlling protein stability, localisation, assembly or activity of the target substrate[1,2,3]
It is no exaggeration to say that at least some key proteins in many seminal pathways and signalling events observed in our body are regulated by ubiquitylation
The activated ubiquitin is transferred to a small ubiquitin-conjugating enzyme (E2), forming a thioester-linked E2-ubiquitin intermediate (E2~Ub)
Summary
The ubiquitin pathway is an ATP-dependent tagging system which regulates a plethora of events in eukaryotic cells by controlling protein stability, localisation, assembly or activity of the target substrate[1,2,3]. It is likely that individual substrate–co-activator binding strength or mode or both regulate the formation of APC/C-E2~Ub and the substrate ubiquitylation Adding yet another level of complexity, the APC/C (E3) consists of multiple subunits and exploits two E2 enzymes (for example, Ube2C and Ube2S) to achieve programmed ubiquitylation (Figure 1C). Classic APC/C inhibition may involve overproduction of the D-box (high dose of the D-box) fragments, which can overwhelm the substrate recognition of Cdc[20] (Figure 4A) and arrest cells at metaphase (by inhibiting APC/C)[101,102,103] This finding suggested that proteins other than cyclin must be degraded to initiate anaphase, leading to the discovery of Cut2/securin[12,13]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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