New open conformation of SMYD3 implicates conformational selection and allostery.
New open conformation of SMYD3 implicates conformational selection and allostery.
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DOI：
10.3934/biophy.2017.1.1
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发表时间：
2017
期刊：
影响因子：
1.5
通讯作者：
Yang Z
中科院分区：
文献类型：
--
作者：
Spellmon N;Sun X;Xue W;Holcomb J;Chakravarthy S;Shang W;Edwards B;Sirinupong N;Li C;Yang Z
SMYD 3在癌细胞活力、粘附、迁移和侵袭中起关键作用。SMYD 3促进诱导型调节性T细胞的形成，并参与减少自身免疫。然而，几乎“封闭”的底物结合位点和体外H3 K4甲基转移酶活性差，模糊了对这种致癌相关蛋白的进一步了解。在这里，我们揭示了SMYD 3可以采用一个“开放”的构象，使用分子动力学模拟和小角X射线散射。这种具有配体结合能力的开放状态与类似晶体结构的闭合状态通过引人注目的蛤壳状叶间动力学相关。这两种状态的特征在于许多不同的结构和动力学差异，并且构象转变途径由C-末端结构域（CTD）的可逆扭转运动介导。从封闭状态到开放状态的自发转变表明SMYD 3功能调节的两种可能的、互不排斥的模型，并且构象选择机制和变构可以调节SMYD 3的催化或配体结合能力。这项研究为SMYD 3在表观遗传基因调控中的令人困惑的作用提供了直接线索。
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.