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Identification and characterization of a novel human methyltransferase modulating Hsp70 protein function through lysine methylation

Jakobsson, Magnus E LU ; Moen, Anders ; Bousset, Luc ; Egge-Jacobsen, Wolfgang ; Kernstock, Stefan ; Melki, Ronald and Falnes, Pål Ø (2013) In Journal of Biological Chemistry 288(39). p.63-27752
Abstract

Hsp70 proteins constitute an evolutionarily conserved protein family of ATP-dependent molecular chaperones involved in a wide range of biological processes. Mammalian Hsp70 proteins are subject to various post-translational modifications, including methylation, but for most of these, a functional role has not been attributed. In this study, we identified the methyltransferase METTL21A as the enzyme responsible for trimethylation of a conserved lysine residue found in several human Hsp70 (HSPA) proteins. This enzyme, denoted by us as HSPA lysine (K) methyltransferase (HSPA-KMT), was found to catalyze trimethylation of various Hsp70 family members both in vitro and in vivo, and the reaction was stimulated by ATP. Furthermore, we show that... (More)

Hsp70 proteins constitute an evolutionarily conserved protein family of ATP-dependent molecular chaperones involved in a wide range of biological processes. Mammalian Hsp70 proteins are subject to various post-translational modifications, including methylation, but for most of these, a functional role has not been attributed. In this study, we identified the methyltransferase METTL21A as the enzyme responsible for trimethylation of a conserved lysine residue found in several human Hsp70 (HSPA) proteins. This enzyme, denoted by us as HSPA lysine (K) methyltransferase (HSPA-KMT), was found to catalyze trimethylation of various Hsp70 family members both in vitro and in vivo, and the reaction was stimulated by ATP. Furthermore, we show that HSPA-KMT exclusively methylates 70-kDa proteins in mammalian protein extracts, demonstrating that it is a highly specific enzyme. Finally, we show that trimethylation of HSPA8 (Hsc70) has functional consequences, as it alters the affinity of the chaperone for both the monomeric and fibrillar forms of the Parkinson disease-associated protein α-synuclein.

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author
publishing date
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Contribution to journal
publication status
published
subject
keywords
Amino Acid Motifs, Amino Acid Sequence, Biomarkers/metabolism, Catalysis, Cloning, Molecular, Computational Biology, DNA Modification Methylases/chemistry, HEK293 Cells, HSP70 Heat-Shock Proteins/metabolism, Humans, Lysine/metabolism, Mass Spectrometry, Molecular Sequence Data, Open Reading Frames, Peptides/metabolism, Protein Binding, Protein Processing, Post-Translational, Recombinant Proteins/metabolism, alpha-Synuclein/metabolism
in
Journal of Biological Chemistry
volume
288
issue
39
pages
12 pages
publisher
ASBMB
external identifiers
  • pmid:23921388
  • scopus:84884772594
ISSN
1083-351X
DOI
10.1074/jbc.M113.483248
language
English
LU publication?
no
id
5d9ab6e6-4bc0-431c-9f48-9f704f4ebd20
date added to LUP
2020-01-13 08:56:32
date last changed
2020-05-26 05:38:08
@article{5d9ab6e6-4bc0-431c-9f48-9f704f4ebd20,
  abstract     = {<p>Hsp70 proteins constitute an evolutionarily conserved protein family of ATP-dependent molecular chaperones involved in a wide range of biological processes. Mammalian Hsp70 proteins are subject to various post-translational modifications, including methylation, but for most of these, a functional role has not been attributed. In this study, we identified the methyltransferase METTL21A as the enzyme responsible for trimethylation of a conserved lysine residue found in several human Hsp70 (HSPA) proteins. This enzyme, denoted by us as HSPA lysine (K) methyltransferase (HSPA-KMT), was found to catalyze trimethylation of various Hsp70 family members both in vitro and in vivo, and the reaction was stimulated by ATP. Furthermore, we show that HSPA-KMT exclusively methylates 70-kDa proteins in mammalian protein extracts, demonstrating that it is a highly specific enzyme. Finally, we show that trimethylation of HSPA8 (Hsc70) has functional consequences, as it alters the affinity of the chaperone for both the monomeric and fibrillar forms of the Parkinson disease-associated protein α-synuclein. </p>},
  author       = {Jakobsson, Magnus E and Moen, Anders and Bousset, Luc and Egge-Jacobsen, Wolfgang and Kernstock, Stefan and Melki, Ronald and Falnes, Pål Ø},
  issn         = {1083-351X},
  language     = {eng},
  month        = {09},
  number       = {39},
  pages        = {63--27752},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Identification and characterization of a novel human methyltransferase modulating Hsp70 protein function through lysine methylation},
  url          = {http://dx.doi.org/10.1074/jbc.M113.483248},
  doi          = {10.1074/jbc.M113.483248},
  volume       = {288},
  year         = {2013},
}