Hepatic cytochrome P450 ubiquitination: conformational phosphodegrons for E2/E3 recognition?
Hepatic endoplasmic reticulum (ER) integral cytochromes P450 (P450s) are monooxygenases engaged in the biotransformation and elimination of endo- as well as xenobiotics. Of the human liver P450s, CYP3A4 is the major and most dominant catalyst responsible for the biotransformation of over 50% of clinically prescribed drugs. CYP2E1 metabolizes smaller molecular weight compounds (EtOH), carcinogens, environmental toxins, and endobiotics, and is justly implicated in various toxigenic/pathogenic mechanisms of human disease. Both P450s are notorious for their potential to generate pathogenic reactive oxygen species (ROS) during futile oxidative cycling and/or oxidative uncoupling. Such ROS not only oxidatively damage the P450 catalytic cage, but on their escape into the cytosol, also the P450 outer surface and any surrounding cell organelles. Given their ER-monotopic topology coupled with this high potential to acquire oxidative lesions in their cytosolic (C) domain, not surprisingly these P450 proteins exhibit shorter lifespans and are excellent prototype substrates of ER-associated degradation ("ERAD-C") pathway. Indeed, we have shown that both CYP3A4 and CYP2E1 incur ERAD-C, during which they are first phosphorylated by protein kinases A and C, which greatly enhance/accelerate their ubiquitination by UBC7/gp78 and UbcH5a/CHIP/Hsp70/Hsp40 E2/E3 ubiquitin ligase complexes. Such P450 phosphorylation occurs on Ser/Thr residues within linear sequences as well as spatially clustered acidic (Asp/Glu) residues. We propose that such S/T phosphorylation within these clusters creates negatively charged patches or conformational phosphodegrons for interaction with positively charged E2/E3 domains. Such P450 S/T phosphorylation we posit serves as a molecular switch to turn on its ubiquitination and ERAD-C.
Department of Cellular & Molecular Pharmacology, University of California, San Francisco, CA; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA; Department of Bioengineering & Therapeutic Sciences, University of California, San Francisco, CA; The Liver Center, University of California, San Francisco, CA.
Maria Almira
MA
Correia
YongQiang
Y
Wang
Sung-Mi
SM
Kim
Shenheng
S
Guan
D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D060746:Endoplasmic Reticulum-Associated Degradation / Q000235:genetics*; D006420:Hemeproteins / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000201:enzymology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000235:genetics*
D006420:Hemeproteins; D017382:Reactive Oxygen Species; D003577:Cytochrome P-450 Enzyme System; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex
Cytochromes P450; E2/E3 ligases; ERAD; ROS; hemeproteins; phosphorylation; proteasomal degradation