Rce1: mechanism and inhibition

Shahienaz E. Hampton, Timothy Dore, Walter K. Schmidt

Research output: Contribution to journalReview article

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.

Original languageEnglish (US)
Pages (from-to)157-174
Number of pages18
JournalCritical Reviews in Biochemistry and Molecular Biology
Volume53
Issue number2
DOIs
StatePublished - Mar 4 2018

Fingerprint

Enzymes
Lamins
Cell signaling
Oxyquinoline
ras Proteins
Aptitude
Monomeric GTP-Binding Proteins
Sequence Alignment
Phosphoprotein Phosphatases
GTP Phosphohydrolases
Substrates
Post Translational Protein Processing
Inhibition (Psychology)
Endoplasmic Reticulum
Protein Kinases
Glutamic Acid
Neoplasms
Protein Isoforms
Proteins
Topology

Keywords

  • CaaX proteins
  • cancer
  • proteases
  • Ras
  • Ras converting enzyme

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Cite this

Rce1 : mechanism and inhibition. / Hampton, Shahienaz E.; Dore, Timothy; Schmidt, Walter K.

In: Critical Reviews in Biochemistry and Molecular Biology, Vol. 53, No. 2, 04.03.2018, p. 157-174.

Research output: Contribution to journalReview article

Hampton, Shahienaz E. ; Dore, Timothy ; Schmidt, Walter K. / Rce1 : mechanism and inhibition. In: Critical Reviews in Biochemistry and Molecular Biology. 2018 ; Vol. 53, No. 2. pp. 157-174.
@article{cba6be311a5b491c97ef93e759e5b69c,
title = "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.",
keywords = "CaaX proteins, cancer, proteases, Ras, Ras converting enzyme",
author = "Hampton, {Shahienaz E.} and Timothy Dore and Schmidt, {Walter K.}",
year = "2018",
month = "3",
day = "4",
doi = "10.1080/10409238.2018.1431606",
language = "English (US)",
volume = "53",
pages = "157--174",
journal = "Critical Reviews in Biochemistry and Molecular Biology",
issn = "1040-9238",
publisher = "Informa Healthcare",
number = "2",

}

TY - JOUR

T1 - Rce1

T2 - mechanism and inhibition

AU - Hampton, Shahienaz E.

AU - Dore, Timothy

AU - Schmidt, Walter K.

PY - 2018/3/4

Y1 - 2018/3/4

N2 - 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.

AB - 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.

KW - CaaX proteins

KW - cancer

KW - proteases

KW - Ras

KW - Ras converting enzyme

UR - http://www.scopus.com/inward/record.url?scp=85043605117&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85043605117&partnerID=8YFLogxK

U2 - 10.1080/10409238.2018.1431606

DO - 10.1080/10409238.2018.1431606

M3 - Review article

C2 - 29424242

AN - SCOPUS:85043605117

VL - 53

SP - 157

EP - 174

JO - Critical Reviews in Biochemistry and Molecular Biology

JF - Critical Reviews in Biochemistry and Molecular Biology

SN - 1040-9238

IS - 2

ER -