Proteomic analyses of the SMYD family interactomes identify HSP90 as a novel target for SMYD2

The SMYD (SET and MYND domain) family of lysine methyltransferases (KMTs) plays pivotal roles in various cellular processes, including gene expression regulation and DNA damage response. Initially identified as genuine histone methyltransferases, specific members of this family have recently been sh...

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Bibliographic Details
Published in:Journal of molecular cell biology 2011-10, Vol.3 (5), p.301-308
Main Authors: Abu-Farha, Mohamed, Lanouette, Sylvain, Elisma, Fred, Tremblay, Véronique, Butson, Jeffery, Figeys, Daniel, Couture, Jean-François
Format: Article
Language:English
Subjects:
HEK293 Cells
Histone Demethylases - genetics
Histone Demethylases - metabolism
Histone-Lysine N-Methyltransferase - chemistry
Histone-Lysine N-Methyltransferase - genetics
Histone-Lysine N-Methyltransferase - metabolism
HSP90 Heat-Shock Proteins - genetics
HSP90 Heat-Shock Proteins - metabolism
Humans
Isoenzymes - chemistry
Isoenzymes - genetics
Isoenzymes - metabolism
Lysine - metabolism
Methylation
Models, Molecular
Multiprotein Complexes - metabolism
Protein Conformation
Protein Interaction Maps
Proteome - analysis
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Summary:The SMYD (SET and MYND domain) family of lysine methyltransferases (KMTs) plays pivotal roles in various cellular processes, including gene expression regulation and DNA damage response. Initially identified as genuine histone methyltransferases, specific members of this family have recently been shown to methylate non-histone proteins such as p53, VEGFR, and the retinoblastoma tumor suppressor (pRb). To gain further functional insights into this family of KMTs, we generated the protein interaction network for three different human SMYD proteins (SMYD2, SMYD3, and SMYD5). Characterization of each SMYD protein network revealed that they associate with both shared and unique sets of proteins. Among those, we found that HSP90 and several of its co-chaperones interact specifically with the tetratrico peptide repeat (TPR)-containing SMYD2 and SMYD3. Moreover, using proteomic and biochemical techniques, we provide evidence that SMYD2 methylates K209 and K615 on HSP90 nucleotide-binding and dimerization domains, respectively. In addition, we found that each methylation site displays unique reactivity in regard to the presence of HSP90 co-chaperones, pH, and demethylation by the lysine amine oxidase LSD1, suggesting that alternative mechanisms control HSP90 methylation by SMYD2. Altogether, this study highlights the ability of SMYD proteins to form unique protein complexes that may underlie their various biological functions and the SMYD2-mediated methylation of the key molecular chaperone HSP90.
ISSN:1674-2788
1759-4685
DOI:10.1093/jmcb/mjr025