Identification and characterization of a novel human methyltransferase modulating Hsp70 protein function through lysine methylation.
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.
From the Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo 0316, Norway and.
Magnus E
ME
Jakobsson
Anders
A
Moen
Luc
L
Bousset
Wolfgang
W
Egge-Jacobsen
Stefan
S
Kernstock
Ronald
R
Melki
Pål Ø
PØ
Falnes
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D015415:Biomarkers / Q000378:metabolism; D002384:Catalysis; D003001:Cloning, Molecular; D019295:Computational Biology; D015254:DNA Modification Methylases / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D016366:Open Reading Frames; D010455:Peptides / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism
D015415:Biomarkers; D018840:HSP70 Heat-Shock Proteins; D010455:Peptides; D011994:Recombinant Proteins; D051844:alpha-Synuclein; D015254:DNA Modification Methylases; C585168:METTL21A protein, human; D008239:Lysine
Enzyme Catalysis; Enzymes; Heat Shock Protein; Molecular Chaperone; Protein Methylation