Structural insights into the C-terminus of the histone-lysine N-methyltransferase NSD3 by small-angle X-ray scattering
NSD3 is a member of six H3K36-specific histone lysine methyltransferases in metazoans. Its overexpression or mutation is implicated in developmental defects and oncogenesis. Aside from the well-characterized catalytic SET domain, NSD3 has multiple clinically relevant potential chromatin-binding moti...
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Frontiers Media S.A.
2024-03-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2024.1191246/full |
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| author | Benny Danilo Belviso Yunpeng Shen Benedetta Carrozzini Masayo Morishita Eric di Luccio Rocco Caliandro |
| author_facet | Benny Danilo Belviso Yunpeng Shen Benedetta Carrozzini Masayo Morishita Eric di Luccio Rocco Caliandro |
| author_sort | Benny Danilo Belviso |
| collection | DOAJ |
| description | NSD3 is a member of six H3K36-specific histone lysine methyltransferases in metazoans. Its overexpression or mutation is implicated in developmental defects and oncogenesis. Aside from the well-characterized catalytic SET domain, NSD3 has multiple clinically relevant potential chromatin-binding motifs, such as the proline–tryptophan–tryptophan–proline (PWWP), the plant homeodomain (PHD), and the adjacent Cys-His-rich domain located at the C-terminus. The crystal structure of the individual domains is available, and this structural knowledge has allowed the designing of potential inhibitors, but the intrinsic flexibility of larger constructs has hindered the characterization of mutual domain conformations. Here, we report the first structural characterization of the NSD3 C-terminal region comprising the PWWP2, SET, and PHD4 domains, which has been achieved at a low resolution in solution by small-angle X-ray scattering (SAXS) data on two multiple-domain NSD3 constructs complemented with size-exclusion chromatography and advanced computational modeling. Structural models predicted by machine learning have been validated in direct space, by comparison with the SAXS-derived molecular envelope, and in reciprocal space, by reproducing the experimental SAXS profile. Selected models have been refined by SAXS-restrained molecular dynamics. This study shows how SAXS data can be used with advanced computational modeling techniques to achieve a detailed structural characterization and sheds light on how NSD3 domains are interconnected in the C-terminus. |
| first_indexed | 2024-03-07T14:02:32Z |
| format | Article |
| id | doaj.art-eaa89727c2e3494d9f4ee6dbff2dfe90 |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-03-07T14:02:32Z |
| publishDate | 2024-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-eaa89727c2e3494d9f4ee6dbff2dfe902024-03-07T05:04:06ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2024-03-011110.3389/fmolb.2024.11912461191246Structural insights into the C-terminus of the histone-lysine N-methyltransferase NSD3 by small-angle X-ray scatteringBenny Danilo Belviso0Yunpeng Shen1Benedetta Carrozzini2Masayo Morishita3Eric di Luccio4Rocco Caliandro5Institute of Crystallography, CNR, Bari, ItalyDepartment of Biotechnology, School of Biological Engineering, Henan University of Technology, Zhengzhou, Henan, ChinaInstitute of Crystallography, CNR, Bari, ItalyDepartment of Genetic Engineering, School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu, Republic of KoreaDepartment of Genetic Engineering, School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu, Republic of KoreaInstitute of Crystallography, CNR, Bari, ItalyNSD3 is a member of six H3K36-specific histone lysine methyltransferases in metazoans. Its overexpression or mutation is implicated in developmental defects and oncogenesis. Aside from the well-characterized catalytic SET domain, NSD3 has multiple clinically relevant potential chromatin-binding motifs, such as the proline–tryptophan–tryptophan–proline (PWWP), the plant homeodomain (PHD), and the adjacent Cys-His-rich domain located at the C-terminus. The crystal structure of the individual domains is available, and this structural knowledge has allowed the designing of potential inhibitors, but the intrinsic flexibility of larger constructs has hindered the characterization of mutual domain conformations. Here, we report the first structural characterization of the NSD3 C-terminal region comprising the PWWP2, SET, and PHD4 domains, which has been achieved at a low resolution in solution by small-angle X-ray scattering (SAXS) data on two multiple-domain NSD3 constructs complemented with size-exclusion chromatography and advanced computational modeling. Structural models predicted by machine learning have been validated in direct space, by comparison with the SAXS-derived molecular envelope, and in reciprocal space, by reproducing the experimental SAXS profile. Selected models have been refined by SAXS-restrained molecular dynamics. This study shows how SAXS data can be used with advanced computational modeling techniques to achieve a detailed structural characterization and sheds light on how NSD3 domains are interconnected in the C-terminus.https://www.frontiersin.org/articles/10.3389/fmolb.2024.1191246/fullnuclear receptor-binding SET domain protein 3small-angle X-ray scatteringcomputational modelingepigenetic cancer therapymolecular dynamics |
| spellingShingle | Benny Danilo Belviso Yunpeng Shen Benedetta Carrozzini Masayo Morishita Eric di Luccio Rocco Caliandro Structural insights into the C-terminus of the histone-lysine N-methyltransferase NSD3 by small-angle X-ray scattering Frontiers in Molecular Biosciences nuclear receptor-binding SET domain protein 3 small-angle X-ray scattering computational modeling epigenetic cancer therapy molecular dynamics |
| title | Structural insights into the C-terminus of the histone-lysine N-methyltransferase NSD3 by small-angle X-ray scattering |
| title_full | Structural insights into the C-terminus of the histone-lysine N-methyltransferase NSD3 by small-angle X-ray scattering |
| title_fullStr | Structural insights into the C-terminus of the histone-lysine N-methyltransferase NSD3 by small-angle X-ray scattering |
| title_full_unstemmed | Structural insights into the C-terminus of the histone-lysine N-methyltransferase NSD3 by small-angle X-ray scattering |
| title_short | Structural insights into the C-terminus of the histone-lysine N-methyltransferase NSD3 by small-angle X-ray scattering |
| title_sort | structural insights into the c terminus of the histone lysine n methyltransferase nsd3 by small angle x ray scattering |
| topic | nuclear receptor-binding SET domain protein 3 small-angle X-ray scattering computational modeling epigenetic cancer therapy molecular dynamics |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2024.1191246/full |
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