Department of Chemistry, Yale University, New Haven, Connecticut, USA.
Institute of Biomolecular Design and Discovery, Yale University, West Haven, Connecticut, USA.
Proteomics. 2023 Dec;23(23-24):e2100211. doi: 10.1002/pmic.202100211. Epub 2023 Aug 21.
Advances in proteogenomic technologies have revealed hundreds to thousands of translated small open reading frames (sORFs) that encode microproteins in genomes across evolutionary space. While many microproteins have now been shown to play critical roles in biology and human disease, a majority of recently identified microproteins have little or no experimental evidence regarding their functionality. Computational tools have some limitations for analysis of short, poorly conserved microprotein sequences, so additional approaches are needed to determine the role of each member of this recently discovered polypeptide class. A currently underexplored avenue in the study of microproteins is structure prediction and determination, which delivers a depth of functional information. In this review, we provide a brief overview of microprotein discovery methods, then examine examples of microprotein structures (and, conversely, intrinsic disorder) that have been experimentally determined using crystallography, cryo-electron microscopy, and NMR, which provide insight into their molecular functions and mechanisms. Additionally, we discuss examples of predicted microprotein structures that have provided insight or context regarding their function. Analysis of microprotein structure at the angstrom level, and confirmation of predicted structures, therefore, has potential to identify translated microproteins that are of biological importance and to provide molecular mechanism for their in vivo roles.
在蛋白质基因组学技术的进步揭示了数百到数千个翻译的小开放阅读框（sORFs），这些阅读框在进化空间的基因组中编码微蛋白。虽然现在已经有许多微蛋白被证明在生物学和人类疾病中发挥着关键作用，但大多数最近发现的微蛋白在其功能方面几乎没有或没有实验证据。计算工具对于分析短的、保护不良的微蛋白序列有一些局限性，因此需要额外的方法来确定这个最近发现的多肽类别的每个成员的作用。微蛋白研究中一个目前尚未充分探索的途径是结构预测和确定，这提供了功能信息的深度。在这篇综述中，我们简要概述了微蛋白的发现方法，然后研究了使用晶体学、低温电子显微镜和 NMR 实验确定的微蛋白结构（反之亦然，固有无序）的例子，这些例子提供了对其分子功能和机制的深入了解。此外，我们还讨论了预测的微蛋白结构的例子，这些例子为它们的功能提供了一些见解或背景。因此，在埃（angstrom）分辨率水平上分析微蛋白结构，并确认预测的结构，有可能识别具有生物学重要性的翻译微蛋白，并为其体内作用提供分子机制。
