NMR structure verifies the eponymous zinc finger domain of transcription factor ZNF750.
NMR structure verifies the eponymous zinc finger domain of transcription factor ZNF750.
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核磁共振结构证实了转录因子ZNF750的同名锌指结构域。
DOI：
10.1016/j.yjsbx.2023.100093
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发表时间：
2023-12
影响因子：
2.9
通讯作者：
Alexandrescu, Andrei T.
中科院分区：
文献类型：
--
作者：
Rua, Antonio J.;Whitehead, Richard D.;Alexandrescu, Andrei T.
关键词：
ZNF750是一种在皮肤分化和癌症中具有功能的转录因子。ZNF750有一个单一的锌指，被归类为“退化”，或不太可能结合锌。核磁共振和CD表明该结构域具有真实稳定的锌指结构。锌的结扎位点为CCHC而不是CCHH， Kd为pM。结构与功能和癌症相关突变有关。ZNF750是一种激活皮肤分化的核转录因子，在几种癌症中具有肿瘤抑制作用。不同寻常的是，ZNF750只有一个锌指（ZNF）结构域Z*，其氨基酸序列与CCHH家族的共识明显不同。由于其序列的差异，Z*被归类为简并，被认为已经失去了与折叠所需的锌离子结合的能力。AlphaFold预测Z*具有低置信度的不规则结构。低置信度预测通常被推断为蛋白质的内在无序区域，如果Z*不结合Zn2+就会出现这种情况。我们利用核磁共振和CD谱分析表明，ZNF750的25-51段对应于Z*结构域折叠成一个明确的反平行ββα三级结构，Zn2+的解离常数为pM，热稳定性为>80°C。在三种可选的Zn2+配体中，Z*使用CCHC而不是预期的CCHH连接基序。最后一个配体的开关保持了经典ZNF基序的折叠拓扑结构和疏水核心。CCHC ZNFs通常与蛋白质相互作用相关，这提高了ZNF750通过其他蛋白质而不是直接与DNA相互作用的可能性。Z*的结构为理解该结构域的功能及其癌症相关突变提供了背景。我们预计目前被归类为简并的其他ZNFs可能是cchc型结构，如Z*。
ZNF750 is a transcription factor with functions in skin differentiation and cancers. ZNF750 has a single zinc-finger classified as ‘degenerate’, or unlikely to bind zinc. NMR and CD show the domain has a genuine and stable zinc finger structure. Ligating site for zinc is CCHC rather than CCHH, Kd is pM. Structure contextualizes function and cancer-linked mutations. ZNF750 is a nuclear transcription factor that activates skin differentiation and has tumor suppressor roles in several cancers. Unusually, ZNF750 has only a single zinc-finger (ZNF) domain, Z*, with an amino acid sequence that differs markedly from the CCHH family consensus. Because of its sequence differences Z* is classified as degenerate, presumed to have lost the ability to bind the zinc ion required for folding. AlphaFold predicts an irregular structure for Z* with low confidence. Low confidence predictions are often inferred to be intrinsically disordered regions of proteins, which would be the case if Z* did not bind Zn2+. We use NMR and CD spectroscopy to show that a 25–51 segment of ZNF750 corresponding to the Z* domain folds into a well-defined antiparallel ββα tertiary structure with a pM dissociation constant for Zn2+ and a thermal stability >80 °C. Of three alternative Zn2+ ligand sets, Z* uses a CCHC rather than the expected CCHH ligating motif. The switch in the last ligand maintains the folding topology and hydrophobic core of the classical ZNF motif. CCHC ZNFs are typically associated with protein–protein interactions, raising the possibility that ZNF750 interacts with DNA through other proteins rather than directly. The structure of Z* provides context for understanding the function of the domain and its cancer-associated mutations. We expect other ZNFs currently classified as degenerate could be CCHC-type structures like Z*.
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