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Unveiling the Biochemistry of the Epigenetic Regulator SMYD3
Alma Mater Studiorum Univ Bologna, Dept Pharm & Biotechnol, Bologna, Italy;CNR, Natl Res Council, Inst Organ Synth & Photoreact ISOF, Bologna, Italy.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.ORCID iD: 0000-0002-1135-2744
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
Alma Mater Studiorum Univ Bologna, Dept Pharm & Biotechnol, Bologna, Italy;St Orsola Marcello Malpighi Hosp, Ctr Appl Biomed Res CRBA, Bologna, Italy.
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2019 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 58, no 35, p. 3634-3645Article in journal (Refereed) Published
Abstract [en]

SET and MYND domain-containing protein 3 (SMYD3) is a lysine methyltransferase that plays a central role in a variety of cancer diseases, exerting its pro-oncogenic activity by methylation of key proteins, of both nuclear and cytoplasmic nature. However, the role of SMYD3 in the initiation and progression of cancer is not yet fully understood and further biochemical characterization is required to support the discovery of therapeutics targeting this enzyme. We have therefore developed robust protocols for production, handling, and crystallization of SMYD3 and biophysical and biochemical assays for clarification of SMYD3 biochemistry and identification of useful lead compounds. Specifically, a time-resolved biosensor assay was developed for kinetic characterization of SMYD3 interactions. Functional differences in SMYD3 interactions with its natural small molecule ligands SAM and SAH were revealed, with SAM forming a very stable complex. A variety of peptides mimicking putative substrates of SMYD3 were explored in order to expose structural features important for recognition. The interaction between SMYD3 and some peptides was influenced by SAM. A nonradioactive SMYD3 activity assay using liquid chromatography-mass spectrometry (LC-MS) analysis explored substrate features of importance also for methylation. Methylation was notable only toward MAP kinase kinase kinase 2 (MAP3K2_K-260)-mimicking peptides, although binary and tertiary complexes were detected also with other peptides. The analysis supported a random bi-bi mechanistic model for SMYD3 methyltransferase catalysis. Our work unveiled complexities in SMYD3 biochemistry and resulted in procedures suitable for further studies and identification of novel starting points for design of effective and specific leads for this potential oncology target.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC , 2019. Vol. 58, no 35, p. 3634-3645
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Biochemistry and Molecular Biology
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URN: urn:nbn:se:uu:diva-394688DOI: 10.1021/acs.biochem.9b00420ISI: 000484643700003PubMedID: 31389685OAI: oai:DiVA.org:uu-394688DiVA, id: diva2:1365424
Funder
EU, Horizon 2020EU, FP7, Seventh Framework Programme, 283570Swedish Research Council, D0571301Available from: 2019-10-24 Created: 2019-10-24 Last updated: 2019-10-24Bibliographically approved

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Talibov, Vladimir OMihalic, FilipDanielson, U. Helena

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