title: New open conformation of SMYD3 implicates conformational selection and allostery.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Spellmon
authors.affiliation: Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Xue
authors.affiliation: Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Holcomb
authors.affiliation: Center for Synchrotron Radiation Research and Instrumentation and Department of Biological and Chemical Sciences, Illinois Institute of Technology, Chicago, Illinois, USA.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Chakravarthy
authors.affiliation: Center for Synchrotron Radiation Research and Instrumentation and Department of Biological and Chemical Sciences, Illinois Institute of Technology, Chicago, Illinois, USA.
authors.forename: Weifeng
authors.initials: W
authors.lastname: Shang
authors.affiliation: Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Edwards
authors.affiliation: Nutraceuticals and Functional Food Research and Development Center, Prince of Songkla University, Hat-Yai, Songkhla, Thailand.
authors.forename: Nualpun
authors.initials: N
authors.lastname: Sirinupong
authors.affiliation: Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA, USA.
authors.forename: Chunying
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Yang
keywords: MYND- and SET-domain containing protein; epigenetics; lysine methyltransferase