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2018 ; 53
(2
): 157-174
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Rce1: mechanism and inhibition
#MMPMID29424242
Hampton SE
; Dore TM
; Schmidt WK
Crit Rev Biochem Mol Biol
2018[Apr]; 53
(2
): 157-174
PMID29424242
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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
?-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 a(2) amino residue in the
Ca(1)a(2)X 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.
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