New open conformation of SMYD3 implicates conformational selection and allostery
| Autor: | Srinivas Chakravarthy, Joshua Holcomb, Brian F.P. Edwards, Wen Xue, Chunying Li, Nualpun Sirinupong, Zhe Yang, Nicholas Spellmon, Weifeng Shang, Xiaonan Sun |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Methyltransferase
Spontaneous transition Allosteric regulation Biophysics Biology Biochemistry Article 03 medical and health sciences Molecular dynamics Closed state 0302 clinical medicine Structural Biology MYND- and SET-domain containing protein Epigenetics lysine methyltransferase lcsh:QH301-705.5 Molecular Biology 030304 developmental biology Regulation of gene expression Genetics 0303 health sciences epigenetics Mechanism (biology) lcsh:Biology (General) 030220 oncology & carcinogenesis |
| Zdroj: | AIMS biophysics AIMS Biophysics, Vol 4, Iss 1, Pp 1-18 (2016) |
| ISSN: | 2377-9098 |
| Popis: | SMYD3 plays a key role in cancer cell viability, adhesion, migration and invasion. SMYD3 promotes formation of inducible regulatory T cells and is involved in reducing autoimmunity. However, the nearly “closed” substrate-binding site and poor in vitro H3K4 methyltransferase activity have obscured further understanding of this oncogenically related protein. Here we reveal that SMYD3 can adopt an “open” conformation using molecular dynamics simulation and small-angle X-ray scattering. This ligand-binding-capable open state is related to the crystal structure-like closed state by a striking clamshell-like inter-lobe dynamics. The two states are characterized by many distinct structural and dynamical differences and the conformational transition pathway is mediated by a reversible twisting motion of the C-terminal domain (CTD). The spontaneous transition from the closed to open states suggests two possible, mutually non-exclusive models for SMYD3 functional regulation and the conformational selection mechanism and allostery may regulate the catalytic or ligand binding competence of SMYD3. This study provides an immediate clue to the puzzling role of SMYD3 in epigenetic gene regulation. |
| Databáze: | OpenAIRE |
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