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.

Functional analysis of the methyltransferase SMYD in the single-cell model organism Tetrahymena thermophila

“…C3, C9 stands for conjugative cells (equal volumes of CU427 and CU428) collected at 3 h and 9 h after mixing, respectively. The normalized gene expression levels, as previously described (Cheng et al 2016 (Donlin et al 2012;Sima and Richter 2018;Spellmon et al 2017). This mass spectrometry result was corroborated by the silver staining of the IP sample ( Fig.…”

SMYD3: An Oncogenic Driver Targeting Epigenetic Regulation and Signaling Pathways

“…The pre-SET, SET, MYND and post-SET domains constitute the N-terminal lobe, while the C-terminal domain contains the TPR region. The N-terminal lobe is crucial for cofactor binding, while the cleft formed by the two lobes creates a crevice crucial for substrate binding [19].…”

Singular value decomposition for the correlation of atomic fluctuations with arbitrary angle

“…The perpendicular correlations were more prominent for widely separated residue pairs. In the DP method, positive and negative correlation coefficients are interpreted as correlated and anticorrelated, respectively, which effectively handles clamshell‐like interlobe dynamics, but is unsuitable for correlations between arbitrarily oriented events such as allostery and other processes involving global protein motions.…”

“…The ensemble character of protein allostery implies that less populated states can significantly affect protein function . Computer simulations, such as molecular dynamics (MD) simulations and more coarse‐grained methods [eg, the anisotropic network model (ANM)] can sample many conformations and provide new insights beyond experimental structure …”

“…26 Computer simulations, such as molecular dynamics (MD) simulations 27,28 and more coarse-grained methods 29 [eg, the anisotropic network model (ANM) 30 ] can sample many conformations and provide new insights beyond experimental structure. 31 A core concept underlying the conformation-based computational methods for allosteric effects is the correlations between different sites in a protein. The analysis reveals that significant inter-residue and inter-domain couplings [32][33][34] as well as the allosteric response [35][36][37] can be inferred from correlated atomic fluctuations.…”