Uncovering human METTL12 as a mitochondrial methyltransferase that modulates citrate synthase activity through metabolite-sensitive lysine methylation
(2017) In Journal of Biological Chemistry 292(43). p.17950-17962- Abstract
Lysine methylation is an important and much-studied posttranslational modification of nuclear and cytosolic proteins but is present also in mitochondria. However, the responsible mitochondrial lysine-specific methyltransferases (KMTs) remain largely elusive. Here, we investigated METTL12, a mitochondrial human S-adenosylmethionine (AdoMet)-dependent methyltransferase and found it to methylate a single protein in mitochondrial extracts, identified as citrate synthase (CS). Using several in vitro and in vivo approaches, we demonstrated that METTL12 methylates CS on Lys-395, which is localized in the CS active site. Interestingly, the METTL12-mediated methylation inhibited CS activity and was blocked by the CS substrate oxaloacetate.... (More)
Lysine methylation is an important and much-studied posttranslational modification of nuclear and cytosolic proteins but is present also in mitochondria. However, the responsible mitochondrial lysine-specific methyltransferases (KMTs) remain largely elusive. Here, we investigated METTL12, a mitochondrial human S-adenosylmethionine (AdoMet)-dependent methyltransferase and found it to methylate a single protein in mitochondrial extracts, identified as citrate synthase (CS). Using several in vitro and in vivo approaches, we demonstrated that METTL12 methylates CS on Lys-395, which is localized in the CS active site. Interestingly, the METTL12-mediated methylation inhibited CS activity and was blocked by the CS substrate oxaloacetate. Moreover, METTL12 was strongly inhibited by the reaction product S-adenosylhomocysteine (AdoHcy). In summary, we have uncovered a novel human mitochondrial KMT that introduces a methyl modification into a metabolic enzyme and whose activity can be modulated by metabolic cues. Based on the established naming nomenclature for similar enzymes, we suggest that METTL12 be renamed CS-KMT (gene name CSKMT).
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- author
- Małecki, Jędrzej ; Jakobsson, Magnus E LU ; Ho, Angela Y Y ; Moen, Anders ; Rustan, Arild C and Falnes, Pål Ø
- publishing date
- 2017-10-27
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Citrate (si)-Synthase/genetics, HeLa Cells, Humans, Methylation, Methyltransferases/classification, Mitochondrial Proteins/classification, Oxaloacetic Acid/metabolism, S-Adenosylhomocysteine/metabolism
- in
- Journal of Biological Chemistry
- volume
- 292
- issue
- 43
- pages
- 13 pages
- publisher
- American Society for Biochemistry and Molecular Biology
- external identifiers
-
- pmid:28887308
- scopus:85032497171
- ISSN
- 1083-351X
- DOI
- 10.1074/jbc.M117.808451
- language
- English
- LU publication?
- no
- additional info
- © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
- id
- cc5cff6f-3f09-4be4-b8f1-fa57e13ba208
- date added to LUP
- 2020-01-13 08:52:54
- date last changed
- 2024-05-29 07:07:22
@article{cc5cff6f-3f09-4be4-b8f1-fa57e13ba208,
abstract = {{<p>Lysine methylation is an important and much-studied posttranslational modification of nuclear and cytosolic proteins but is present also in mitochondria. However, the responsible mitochondrial lysine-specific methyltransferases (KMTs) remain largely elusive. Here, we investigated METTL12, a mitochondrial human S-adenosylmethionine (AdoMet)-dependent methyltransferase and found it to methylate a single protein in mitochondrial extracts, identified as citrate synthase (CS). Using several in vitro and in vivo approaches, we demonstrated that METTL12 methylates CS on Lys-395, which is localized in the CS active site. Interestingly, the METTL12-mediated methylation inhibited CS activity and was blocked by the CS substrate oxaloacetate. Moreover, METTL12 was strongly inhibited by the reaction product S-adenosylhomocysteine (AdoHcy). In summary, we have uncovered a novel human mitochondrial KMT that introduces a methyl modification into a metabolic enzyme and whose activity can be modulated by metabolic cues. Based on the established naming nomenclature for similar enzymes, we suggest that METTL12 be renamed CS-KMT (gene name CSKMT).</p>}},
author = {{Małecki, Jędrzej and Jakobsson, Magnus E and Ho, Angela Y Y and Moen, Anders and Rustan, Arild C and Falnes, Pål Ø}},
issn = {{1083-351X}},
keywords = {{Citrate (si)-Synthase/genetics; HeLa Cells; Humans; Methylation; Methyltransferases/classification; Mitochondrial Proteins/classification; Oxaloacetic Acid/metabolism; S-Adenosylhomocysteine/metabolism}},
language = {{eng}},
month = {{10}},
number = {{43}},
pages = {{17950--17962}},
publisher = {{American Society for Biochemistry and Molecular Biology}},
series = {{Journal of Biological Chemistry}},
title = {{Uncovering human METTL12 as a mitochondrial methyltransferase that modulates citrate synthase activity through metabolite-sensitive lysine methylation}},
url = {{http://dx.doi.org/10.1074/jbc.M117.808451}},
doi = {{10.1074/jbc.M117.808451}},
volume = {{292}},
year = {{2017}},
}