The Degron Architecture of Squalene Monooxygenase and How Specific Lipids Calibrate Levels of This Key Cholesterol Synth
Cholesterol synthesis is a fundamental process that contributes to cellular cholesterol homeostasis. Cells execute transcriptional and post-translational mechanisms to control the abundance of enzymes of the cholesterol synthesis pathway, consequently aff
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The Degron Architecture of Squalene Monooxygenase and How Specific Lipids Calibrate Levels of This Key Cholesterol Synthesis Enzyme Ngee Kiat Chua and Andrew J. Brown Abstract
non-canonical ubiquitination on serine, a relatively uncommon attachment site for ubiquitination. The structure of the catalytic domain of SM has been solved, providing insights into the catalytic mechanisms and modes of inhibition by well-known SM inhibitors, some of which have been effective in lowering cholesterol levels in animal models. Certain human cancers have been linked to dysregulation of SM levels and activity, further emphasizing the relevance of SM in health and disease.
Cholesterol synthesis is a fundamental process that contributes to cellular cholesterol homeostasis. Cells execute transcriptional and posttranslational mechanisms to control the abundance of enzymes of the cholesterol synthesis pathway, consequently affecting cholesterol production. One such highly tuned enzyme is squalene monooxygenase (SM), which catalyzes a rate-limiting step in the pathway. A well-characterized mechanism is the cholesterol-mediated degradation of SM. Notably, lipids (cholesterol, plasmalogens, squalene, and unsaturated fatty acids) can act as cellular signals that either promote or reduce SM degradation. The N-terminal region of SM consists of the shortest known cholesterol-responsive degron, characterized by atypical membrane anchoring structures, namely a re-entrant loop and an amphipathic helix. SM also undergoes
Keywords
Cholesterol synthesis · Degron · Endoplasmic reticulum-associated degradation (ERAD) · Squalene · Squalene monooxygenase · Ubiquitin
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N. K. Chua (*) Ubiquitin Signalling Division, The Walter and Eliza Hall Institute for Medical Research, Melbourne, VIC, Australia e-mail: [email protected] A. J. Brown (*) School of Biotechnology and Biomolecular Sciences, University of New South Wales (UNSW), Sydney, NSW, Australia e-mail: [email protected]
Introduction
The mevalonate pathway leads to the formation of essential metabolites, including ubiquinone, dolichol and cholesterol (Brown and Sharpe 2016). Cellular regulation of enzymes within the pathway is achieved by control of gene expression and protein turnover; this allows the mevalonate pathway to be less or more active, depending on the metabolic needs of the cell (Brown and Sharpe 2016).
N. K. Chua and A. J. Brown
In addition, the pathway is of clinical importance in cardiovascular disease; statins (a class of cholesterol-lowering drugs) inhibit this pathway by inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), the first ratelimiting enzyme of the pathway (Buhaescu and Izzedine 2007; Goldstein and Brown 2015). The pathway is also of significant interest for research related to cancers, immunity and Alzheimer’s disease (Buhaescu and Izzedine 2007; Mullen et al. 2016). Genes encoding the enzymes of the mevalonate pathway are transcriptionally controlled by transcription factors known as the Sterol Regulatory Element Binding Proteins (Brown and
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