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Williams–Beuren syndrome‐related methyltransferase WBSCR27: cofactor binding and cleavage
- Source :
- The FEBS Journal. 287:5375-5393
- Publication Year :
- 2020
- Publisher :
- Wiley, 2020.
-
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'-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'-adenosyl)-l-methionine (SAM) and its metabolic products - SAH, 5'-deoxy-5'-methylthioadenosine (MTA) and 5'-deoxyadenosine (5'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'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.
- Subjects :
- 0301 basic medicine
S-Adenosylmethionine
Methyltransferase
Protein Conformation
Biochemistry
Cofactor
Mice
03 medical and health sciences
Apoenzymes
0302 clinical medicine
Animals
Molecular Biology
Protein secondary structure
chemistry.chemical_classification
Cofactor binding
Thionucleosides
Deoxyadenosines
biology
Isothermal titration calorimetry
Methyltransferases
Cell Biology
Methylation
S-Adenosylhomocysteine
Nucleosidases
030104 developmental biology
Enzyme
chemistry
030220 oncology & carcinogenesis
biology.protein
Subjects
Details
- ISSN :
- 17424658 and 1742464X
- Volume :
- 287
- Database :
- OpenAIRE
- Journal :
- The FEBS Journal
- Accession number :
- edsair.doi.dedup.....3fe3929fbe01c88f5e13bf9c9772d587