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Nature. 2018 Jan 25;553(7689):526-529. doi: 10.1038/nature25439. Epub 2018 Jan 17.

Atomic structure of the eukaryotic intramembrane RAS methyltransferase ICMT.

Author information

1
Structural Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.
2
Graduate Program in Biochemistry and Structural Biology, Cell and Developmental Biology, and Molecular Biology, Weill Cornell Medicine Graduate School of Medical Sciences, 1300 York Avenue, New York, New York 10065, USA.
3
Perlmutter Cancer Center, New York University Langone Medical Center, 430 East 29th Street, New York, New York 10016, USA.
4
Department of Medicine, New York University Langone Medical Center, 430 East 29th Street, New York, New York 10016, USA.
5
Department of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, 430 East 29th Street, New York, New York 10016, USA.

Abstract

The maturation of RAS GTPases and approximately 200 other cellular CAAX proteins involves three enzymatic steps: addition of a farnesyl or geranylgeranyl prenyl lipid to the cysteine (C) in the C-terminal CAAX motif, proteolytic cleavage of the AAX residues and methylation of the exposed prenylcysteine residue at its terminal carboxylate. This final step is catalysed by isoprenylcysteine carboxyl methyltransferase (ICMT), a eukaryote-specific integral membrane enzyme that resides in the endoplasmic reticulum. ICMT is the only cellular enzyme that is known to methylate prenylcysteine substrates; methylation is important for the biological functions of these substrates, such as the membrane localization and subsequent activity of RAS, prelamin A and RAB. Inhibition of ICMT has potential for combating progeria and cancer. Here we present an X-ray structure of ICMT, in complex with its cofactor, an ordered lipid molecule and a monobody inhibitor, at 2.3 Å resolution. The active site spans cytosolic and membrane-exposed regions, indicating distinct entry routes for the cytosolic methyl donor, S-adenosyl-l-methionine, and for prenylcysteine substrates, which are associated with the endoplasmic reticulum membrane. The structure suggests how ICMT overcomes the topographical challenge and unfavourable energetics of bringing two reactants that have different cellular localizations together in a membrane environment-a relatively uncharacterized but defining feature of many integral membrane enzymes.

PMID:
29342140
PMCID:
PMC5785467
DOI:
10.1038/nature25439
[Indexed for MEDLINE]
Free PMC Article

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