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首页> 外文期刊>Journal of Molecular Biology >Structural Basis of Protein Arginine Methyltransferase Activation by a Catalytically Dead Homolog (Prozyme)
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Structural Basis of Protein Arginine Methyltransferase Activation by a Catalytically Dead Homolog (Prozyme)

机译：蛋白质精氨酸甲基转移酶活性的结构基于催化死子同源物激活（prozyme）

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摘要

Prozymes are pseudoenzymes that stimulate the function of weakly active enzymes through complex formation. The major Trypanosome brucei protein arginine methyltransferase, TbPRMT1 enzyme (ENZ), requires TbPRMT1 prozyme (PRO) to form an active heterotetrameric complex. Here, we present the X-ray crystal structure of the TbPRMT1 ENZ-Delta 52PRO tetrameric complex with the cofactor product S-adenosyl-L-homocysteine (AdoHcy) at 2.4 angstrom resolution. The individual ENZ and PRO units adopt the highly-conserved PRMT domain architecture and form an antiparallel heterodimer that corresponds to the canonical homodimer observed in all previously reported PRMTs. In turn, two such heterodimers assemble into a tetramer both in the crystal and in solution with twofold rotational symmetry. ENZ is unstable in absence of PRO and incapable of forming a homodimer due to a steric clash of an ENZ-specific tyrosine within the dimerization arm, rationalizing why PRO is required to complement ENZ to form a PRMT dimer that is necessary, but not sufficient for PRMT activity. The PRO structure deviates from other, active PRMTs in that it lacks the conserved eta 2 3(10)-helix within the Rossmann fold, abolishing cofactor binding. In addition to its chaperone function for ENZ, PRO substantially contributes to substrate binding. Heterotetramerization is required for catalysis, as heterodimeric ENZ-PRO mutants lack binding affinity and methyltransferase activity toward the substrate protein TbRGG1. Together, we provide a structural basis for TbPRMT1 ENZ activation by PRO heterotetramer formation, which is conserved across all kinetoplastids, and describe a chaperone function of the TbPRMT1 prozyme, which represents a novel mode of PRMT regulation. (C) 2019 Elsevier Ltd. All rights reserved.
机译：逐酶是伪酶，其通过复杂的形成刺激弱活性酶的功能。主要的锥虫组体Brucei蛋白质精氨酸甲基转移酶Tbprmt1酶（ENZ）需要Tbprmt1 prozyme（pro）以形成活性异淀粉。这里，我们将Tbprmt1 enz-delta 52pro四聚体络合物的X射线晶体结构与辅因子产物S-腺苷-1-同型半胱氨酸（Adohcy）呈现为2.4埃分辨率。个别enz和Pro单元采用高度保守的PRMT域架构，并形成反平行的异二聚体，其对应于在所有先前报告的PRMT中观察到的规范同源体。反过来，两种这样的异二聚体组装成晶体和双重旋转对称的四聚体。由于在二聚化臂内的eNZ特异性酪氨酸的空间冲突中，不能形成同源过二聚体的eNZ是不稳定的，因此使PRO为赋予ENZ的特定化以形成所需的PRMT二聚体，但不足以PRMT活动。 Pro结构偏离其他活性的PRMT，因为它在Rossmann折叠内缺乏保守的ETA 2 3（10） - ε，消除了辅因子结合。除了eNZ的伴侣函数之外，Pro基本上有助于底物结合。催化需要异质异位化，因为异二聚体enz-Pro突变体缺乏对底物蛋白TBRGG1的结合亲和力和甲基转移酶活性。我们在一起，为Pro异质特征形成的TBPRMT1 enz活化提供了一种结构基础，所述促型异质特异性组形成，其在所有kinetoploplys上保守，并描述了Tbprmt1 prozyme的伴随伴随的PRMT调节模式。 （c）2019 Elsevier Ltd.保留所有权利。

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