Hepatic cytochromes P450: structural degrons and barcodes, posttranslational modifications and cellular adapters in the ERAD-endgame.
The endoplasmic reticulum (ER)-anchored hepatic cytochromes P450 (P450s) are enzymes that metabolize endo- and xenobiotics i.e. drugs, carcinogens, toxins, natural and chemical products. These agents modulate liver P450 content through increased synthesis or reduction via inactivation and/or proteolytic degradation, resulting in clinically significant drug-drug interactions. P450 proteolytic degradation occurs via ER-associated degradation (ERAD) involving either of two distinct routes: Ubiquitin (Ub)-dependent 26S proteasomal degradation (ERAD/UPD) or autophagic lysosomal degradation (ERAD/ALD). CYP3A4, the major human liver/intestinal P450, and the fast-turnover CYP2E1 species are degraded via ERAD/UPD entailing multisite protein phosphorylation and subsequent ubiquitination by gp78 and CHIP E3 Ub-ligases. We are gaining insight into the nature of the structural determinants involved in CYP3A4 and CYP2E1 molecular recognition in ERAD/UPD [i.e. K48-linked polyUb chains and linear and/or "conformational" phosphodegrons consisting either of consecutive sequences on surface loops and/or disordered regions, or structurally-assembled surface clusters of negatively charged acidic (Asp/Glu) and phosphorylated (Ser/Thr) residues, within or vicinal to which, Lys-residues are targeted for ubiquitination]. Structural inspection of select human liver P450s reveals that such linear or conformational phosphodegrons may indeed be a common P450-ERAD/UPD feature. By contrast, although many P450s such as the slow-turnover CYP2E1 species and rat liver CYP2B1 and CYP2C11 are degraded via ERAD/ALD, little is known about the mechanism of their ALD-targeting. On the basis of our current knowledge of ALD-substrate targeting, we propose a tripartite conjunction of K63-linked Ub-chains, P450 structural "LIR" motifs and selective cellular "cargo receptors" as plausible P450-ALD determinants.
a Department of Cellular & Molecular Pharmacology , University of California San Francisco , San Francisco , CA , USA ;
Sung-Mi
SM
Kim
a Department of Cellular & Molecular Pharmacology , University of California San Francisco , San Francisco , CA , USA ;
YongQiang
Y
Wang
a Department of Cellular & Molecular Pharmacology , University of California San Francisco , San Francisco , CA , USA ;
Noushin
N
Nabavi
a Department of Cellular & Molecular Pharmacology , University of California San Francisco , San Francisco , CA , USA ;
Yi
Y
Liu
a Department of Cellular & Molecular Pharmacology , University of California San Francisco , San Francisco , CA , USA ;|b Department of Pharmaceutical Chemistry , University of California San Francisco , San Francisco , CA , USA ;|c Department of Bioengineering and Therapeutic Sciences , University of California San Francisco , San Francisco , CA , USA ;|d The Liver Center, University of California San Francisco , San Francisco , CA , USA.
Maria Almira
MA
Correia
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D060746:Endoplasmic Reticulum-Associated Degradation; D006801:Humans; D008099:Liver / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008954:Models, Biological; D059748:Proteolysis; D060285:Receptors, Autocrine Motility Factor / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
D003577:Cytochrome P-450 Enzyme System; C555000:AMFR protein, human; D060285:Receptors, Autocrine Motility Factor; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases
26S proteasome; CHIP; Cytochromes P450; E2/E3 ubiquitin ligases; ERAD; K48 & K63 ubiquitination; autophagic lysosomal degradation; gp78 E3; p62; p97; phosphodegrons