Williams-Beuren Syndrome Related Methyltransferase WBSCR27: From Structure to Possible Function

Sofia S Mariasina; Chi-Fon Chang; Tsimafei L Navalayeu; Anastasia A Chugunova; Sergey V Efimov; Viktor G Zgoda; Vasily A Ivlev; Olga A Dontsova; Petr V Sergiev; Vladimir I Polshakov

doi:10.3389/fmolb.2022.865743

Williams-Beuren Syndrome Related Methyltransferase WBSCR27: From Structure to Possible Function

Front Mol Biosci. 2022 Jun 15:9:865743. doi: 10.3389/fmolb.2022.865743. eCollection 2022.

Authors

Sofia S Mariasina^{1

2}, Chi-Fon Chang³, Tsimafei L Navalayeu⁴, Anastasia A Chugunova⁴, Sergey V Efimov⁵, Viktor G Zgoda⁶, Vasily A Ivlev⁷, Olga A Dontsova^{4

8}, Petr V Sergiev^{2

4

8}, Vladimir I Polshakov¹

Affiliations

¹ Faculty of Fundamental Medicine, M.V. Lomonosov Moscow State University, Moscow, Russia.
² Institute of Functional Genomics, M.V. Lomonosov Moscow State University, Moscow, Russia.
³ Genomics Research Center, Academia Sinica, Taipei, Taiwan.
⁴ Chemical Department, M.V. Lomonosov Moscow State University, Moscow, Russia.
⁵ NMR Laboratory, Institute of Physics, Kazan Federal University, Kazan, Russia.
⁶ Institute of Biomedical Chemistry, Moscow, Russia.
⁷ Pharmacy Resource Center, RUDN University, Moscow, Russia.
⁸ Skolkovo Institute of Science and Technology, Moscow, Russia.

Abstract

Williams-Beuren syndrome (WBS) is a genetic disorder associated with the hemizygous deletion of several genes in chromosome 7, encoding 26 proteins. Malfunction of these proteins induce multisystemic failure in an organism. While biological functions of most proteins are more or less established, the one of methyltransferase WBSCR27 remains elusive. To find the substrate of methylation catalyzed by WBSCR27 we constructed mouse cell lines with a Wbscr27 gene knockout and studied the obtained cells using several molecular biology and mass spectrometry techniques. We attempted to pinpoint the methylation target among the RNAs and proteins, but in all cases neither a direct substrate has been identified nor the protein partners have been detected. To reveal the nature of the putative methylation substrate we determined the solution structure and studied the conformational dynamic properties of WBSCR27 in apo state and in complex with S-adenosyl-L-homocysteine (SAH). The protein core was found to form a canonical Rossman fold common for Class I methyltransferases. N-terminus of the protein and the β6-β7 loop were disordered in apo-form, but binding of SAH induced the transition of these fragments to a well-formed substrate binding site. Analyzing the structure of this binding site allows us to suggest potential substrates of WBSCR27 methylation to be probed in further research.

Keywords: NMR; S-adenosyl-L-homocysteine (SAH); Williams-Beuren syndrome (WBS); methyltransferase (MTase); protein dynamics; protein structure in solution.