Structural analyses of inositol phosphate second messengers bound to signaling effector proteins
Structural analyses of inositol phosphate second messengers bound to signaling effector proteins
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DOI：
10.1016/j.jbior.2019.100667
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发表时间：
2020-01-01
影响因子：
--
通讯作者：
Blind, Raymond D.
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文献类型：
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作者：
Blind, Raymond D.
高级肌醇磷酸第二信使肌醇四磷酸（IP 4）、肌醇五磷酸（IPS）和肌醇六磷酸（IP 6）是重要的信号分子，其调节DNA损伤修复、粘附素动力学、RNA编辑、逆转录病毒组装、核转运、磷酸化、乙酰化、巴豆酰化和泛素化。这种功能的多样性使得理解肌醇多磷酸盐如何调节细胞过程具有挑战性。然而，一些肌醇磷酸已意外地发现在X-射线晶体结构，偶尔揭示效应蛋白调节的结构和机制的细节之前，功能的后果已经描述。这篇评论突出了描述肌醇磷酸和蛋白质效应器之间的相互作用的晶体结构的采样。该列表包括RNA编辑酶“作用于RNA 2的腺苷脱氨酶”（ADAR 2）、粘附素动力学的Pds 5 B调节剂、1类组蛋白脱乙酰酶（HDAC）HDAC 1和HDAC 3以及布鲁顿酪氨酸激酶（Btk）的PH结构域。负责高级肌醇磷酸合成的最重要的酶之一是肌醇多磷酸多激酶（IPMK），其在肌醇和磷酸肌醇信号传导中起双重作用。磷脂酰肌醇脂质结合蛋白的结构也揭示了蛋白效应物调节的新方面，如由核受体类固醇生成因子-1（SF-1，NR 5A 2）和肝受体同源物-1（LRH-1，NR 5A 2）介导的。总之，这些研究强调了效应蛋白和磷酸肌醇小信号分子之间结合相互作用的结构多样性，并进一步支持详细的结构研究可以导致新的生物学发现。
The higher-order inositol phosphate second messengers inositol tetrakisphosphate (IP4), inositol pentakisphosphate (IPS) and inositol hexakisphosphate (IP6) are important signaling molecules that regulate DNA-damage repair, cohesin dynamics, RNA-editing, retroviral assembly, nuclear transport, phosphorylation, acetylation, crotonylation, and ubiquitination. This functional diversity has made understanding how inositol polyphosphates regulate cellular processes challenging to dissect. However, some inositol phosphates have been unexpectedly found in X-ray crystal structures, occasionally revealing structural and mechanistic details of effector protein regulation before functional consequences have been described. This review highlights a sampling of crystal structures describing the interaction between inositol phosphates and protein effectors. This list includes the RNA editing enzyme "adenosine deaminase that acts on RNA 2" (ADAR2), the Pds5B regulator of cohesin dynamics, the class 1 histone deacetylases (HDACs) HDAC1 and HDAC3, and the PH domain of Bruton's tyrosine kinase (Btk). One of the most important enzymes responsible for higher-order inositol phosphate synthesis is inositol polyphosphate multikinase (IPMK), which plays dual roles in both inositol and phosphoinositide signaling. Structures of phosphoinositide lipid binding proteins have also revealed new aspects of protein effector regulation, as mediated by the nuclear receptors Steroidogenic Factor-1 (SF-1, NR5A2) and Liver Receptor Homolog-1 (LRH-1, NR5A2). Together, these studies underscore the structural diversity in binding interactions between effector proteins and inositol phosphate small signaling molecules, and further support that detailed structural studies can lead to new biological discovery.