Rce1: mechanism and inhibition

Abstract

Ras converting enzyme 1 (Rce1) is an integral membrane endoprotease localized to the endoplasmic reticulum that mediates the cleavage of the carboxyl-terminal three amino acids from CaaX proteins, whose members play important roles in cell signaling processes. Examples include the Ras family of small GTPases, the γ-subunit of heterotrimeric GTPases, nuclear lamins, and protein kinases and phosphatases. CaaX proteins, especially Ras, have been implicated in cancer, and understanding the post-translational modifications of CaaX proteins would provide insight into their biological function and regulation. Many proteolytic mechanisms have been proposed for Rce1, but sequence alignment, mutational studies, topology, and recent crystallographic data point to a novel mechanism involving a glutamate-activated water and an oxyanion hole. Studies using in vivo and in vitro reporters of Rce1 activity have revealed that the enzyme cleaves only prenylated substrates and the identity of the a2 amino residue in the Ca1a2X sequence is most critical for recognition, preferring Ile, Leu, or Val. Substrate mimetics can be somewhat effective inhibitors of Rce1 in vitro. Small-molecule inhibitor discovery is currently limited by the lack of structural information on a eukaryotic enzyme, but a set of 8-hydroxyquinoline derivatives has demonstrated an ability to mislocalize all three mammalian Ras isoforms, giving optimism that potent, selective inhibitors might be developed. Much remains to be discovered regarding cleavage specificity, the impact of chemical inhibition, and the potential of Rce1 as a therapeutic target, not only for cancer, but also for other diseases.

Rce1 suppresses invasion and metastasis of hepatocellular carcinoma via epithelial‐mesenchymal transition induced by the TGF‐β1/H‐Ras signaling pathway

“…Manolaridis et al () and Hampton et al () have verified that Rce1 is an isoprenyl endopeptidase that localizes to the endoplasmic reticulum to remove the carboxyl‐terminal three amino acids via hydrolyzation of C15 or C20 isoprenylation of the cysteine in CAAX. Bergo et al () believe that suppression of Rce1 activity is associated with Ras mislocalization, diminished growth of Ras‐transformed fibroblasts in culture and in nude mice, and hypersensitivity to farnesyl and geranylgeranyl transferase inhibitors (FTIs).…”

Targeting RAS‐converting enzyme 1 overcomes senescence and improves progeria‐like phenotypes of ZMPSTE24 deficiency

“…A specific RCE1 inhibitor would be required to determine whether targeting this enzyme pharmacologically could be useful in treating disorders of ZMPSTE24 deficiency—a strategy that would be relevant for MAD‐B and the extremely rare atypical form of HGPS, but not for RD as it is lethal at birth (Hampton, Dore, & Schmidt, 2018). However, such an inhibitor would not be required to completely inhibit RCE1 because 65% of reduced Rce1 expression was sufficient to double the median survival of Zmpste24 ‐deficient mice.…”

CaaX-Like Protease of Cyanobacterial Origin Is Required for Complex Plastid Biogenesis in Malaria Parasites

“…The AMR4 mutation identified in our screen (S347G) is near the active site of the gene’s only annotated domain, a CaaX protease and bacteriocin processing (CPBP) domain. Mutagenesis and structural studies of CPBP domains indicate a catalytic mechanism in which a conserved glutamate activates a nucleophilic water molecule for proteolysis ( 27 – 30 ). Mutation of this catalytic glutamate was shown to completely abolish protease function without disrupting the stability or conformation of the protein ( 29 ).…”