Williams–Beuren syndrome‐related methyltransferase WBSCR27: cofactor binding and cleavage

Abstract

Williams-Beuren syndrome, characterized by numerous physiological and mental problems, is caused by the heterozygous deletion of chromosome region 7q11.23, which results in the disappearance of 26 protein-coding genes. Protein WBSCR27 is a product of one of these genes whose biological function has not yet been established and for which structural information has been absent until now. Using NMR, we investigated the structural and functional properties of murine WBSCR27. For protein in the apo form and in a complex with S-(5 0-adenosyl)-L-homocysteine (SAH), a complete NMR resonance assignment has been obtained and the secondary structure has been determined. This information allows us to attribute WBSCR27 to Class I methyltransferases. The interaction of WBSCR27 with the cofactor S-(5 0-adenosyl)-L-methionine (SAM) and its metabolic products-SAH, 5 0-deoxy-5 0-methylthioadenosine (MTA) and 5 0-deoxyadenosine (5 0 dAdo)was studied by NMR and isothermal titration calorimetry. SAH binds WBSCR27 much tighter than SAM, leaving open the question of cofactor turnover in the methylation reaction. One possible answer to this question is the presence of weak but detectable nucleosidase activity for WBSCR27. We found that the enzyme catalyses the cleavage of the adenine moiety from SAH, MTA and 5 0 dAdo, similar to the action of bacterial SAH/MTA nucleosidases. We also found that the binding of SAM or SAH causes a significant change in the structure of WBSCR27 and in the conformational mobility of the protein fragments, which can be attributed to the substrate recognition site. This indicates that the binding of the cofactor modulates the folding of the substrate-recognizing region of the enzyme.

Multi-omics integration of methyltransferase-like protein family reveals clinical outcomes and functional signatures in human cancer

“…A very recent study revealed that METTL18 is a histidine methyltransferase that regulates translation in cancer cells 9 . In addition to cancer, mutations and copy number alterations in METTLs can cause multiple neurological and multisystemic disorders 10 , 11 . Thus, previous studies demonstrate that METTLs are important regulators of cellular processes, which, if derailed, may result in the development of a multitude of diseases and disorders, including cancer.…”

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

“…Earlier, we found that both SAM and SAH strongly bind to WBSCR27 ( Mariasina et al, 2020 ). Relatively small changes in the chemical shifts of the signals of the residues in the binding site of these two ligands indicate that the structure of WBSCR27-SAM and WBSCR27-SAH complexes is similar ( Mariasina et al, 2020 ).…”

“…Earlier we reported the backbone and side chain signal assignments for the complex SAH-WBSCR27 (BMRB-27417, Mariasina et al, 2018 ) and for the apo form of the protein (BMRB-27578, Mariasina et al, 2020 ) and deposited these data in BioMagResBank ( https://bmrb.io ). This information was used to determine NMR restraints.…”

“…In our previous work ( Mariasina et al, 2020 ) we demonstrated that WBSCR27 effectively interacts with the cofactor S-(5′-adenosyl)-L-methionine (SAM) and has a canonical Rossman fold, typical of Class I MTases. This information supports the bioinformatic assignment of WBSCR27 to MTases; however, the substrate of methylation catalyzed by this enzyme is still unknown.…”

Bioinformatic analysis of methyltransferase-like protein family reveals clinical and functional outcomes in human cancer

“…Additionally, biallelic frameshift variants in the rRNA m 6 A methyltransferase METTL5 cause intellectual disability and microcephaly 14 . Heterozygous deletion of chromosome region 7q11.23, which contains METTL27 (also known as WBSCR27), causes Williams-Beuren syndrome (WBS), a neurodevelopmental and multisystemic disease 15 . Thus, previous studies demonstrate that METTLs are important regulators of cellular processes, which if derailed, may result in the development of a multitude of disease and disorders, including cancer.…”