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Mechanism of isoprenylcysteine carboxyl methylation from the crystal structure of the integral membrane methyltransferase ICMT

DOI: 10.1016/j.molcel.2011.10.020 DOI Help
PMID: 22195972 PMID Help

Authors: Jing Yang (Chester Beatty Laboratories) , Kiran Kulkarni (Chester Beatty Laboratories) , Ioannis Manolaridis (Chester Beatty Laboratories) , Ziguo Zhang (Chester Beatty Laboratories) , Roger b. Dodd (Chester Beatty Laboratories) , Corine Mas-Droux (Chester Beatty Laboratories) , David Barford (Chester Beatty Laboratories)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Molecular Cell , VOL 44 (6) , PAGES 997 - 1004

State: Published (Approved)
Published: December 2011
Diamond Proposal Number(s): 6385

Abstract: The posttranslational modification of C-terminal CAAX motifs in proteins such as Ras, most Rho GTPases, and G protein γ subunits, plays an essential role in determining their subcellular localization and correct biological function. An integral membrane methyltransferase, isoprenylcysteine carboxyl methyltransferase (ICMT), catalyzes the final step of CAAX processing after prenylation of the cysteine residue and endoproteolysis of the –AAX motif. We have determined the crystal structure of a prokaryotic ICMT ortholog, revealing a markedly different architecture from conventional methyltransferases that utilize S-adenosyl-L-methionine (SAM) as a cofactor. ICMT comprises a core of five transmembrane α helices and a cofactor-binding pocket enclosed within a highly conserved C-terminal catalytic subdomain. A tunnel linking the reactive methyl group of SAM to the inner membrane provides access for the prenyl lipid substrate. This study explains how an integral membrane methyltransferase achieves recognition of both a hydrophilic cofactor and a lipophilic prenyl group attached to a polar protein substrate.

Journal Keywords: Crystallography; X-Ray; Cytosol; Lipid; Methanosarcina; Methylation; Models; Molecular; Mutation; Protein; Tertiary; S-Adenosylmethionine; Structure-Activity; Substrate Specificity

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography

Added On: 28/03/2012 11:51

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)