Department of Biochemistry, Molecular Biology and Biotechnology, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, Wrocław, 50-370, Poland.
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawińskiego 5a, Warsaw, 02-106, Poland.
Cell Commun Signal. 2024 May 29;22(1):298. doi: 10.1186/s12964-024-01675-x.
Nucleobindin-2 (Nucb2) and nesfatin-1 (N1) are widely distributed hormones that regulate numerous physiological processes, from energy homeostasis to carcinogenesis. However, the role of nesfatin-2 (N2), the second product of Nucb2 proteolytic processing, remains elusive. To elucidate the relationship between the structure and function of nesfatins, we investigated the properties of chicken and human homologs of N1, as well as a fragment of Nucb2 consisting of N1 and N2 conjoined in a head-to-tail manner (N1/2).
Our findings indicate that Zn(II) sensing, in the case of N1, is conserved between chicken and human species. However, the data presented here reveal significant differences in the molecular features of the analyzed peptides, particularly in the presence of Zn(II). We demonstrated that Zn(II) has a Janus effect on the M30 region (a crucial anorexigenic core) of N1 and N1/2. In N1 homologs, Zn(II) binding results in the concealment of the M30 region driven by a disorder-to-order transition and adoption of the amyloid fold. In contrast, in N1/2 molecules, Zn(II) binding causes the exposure of the M30 region and its destabilization, resulting in strong exposure of the region recognized by prohormone convertases within the N1/2 molecule.
In conclusion, we found that Zn(II) binding is conserved between chicken and human N1. However, despite the high homology of chicken and human N1, their interaction modes with Zn(II) appear to differ. Furthermore, Zn(II) binding might be essential for regulating the function of nesfatins by spatiotemporally hindering the N1 anorexigenic M30 core and concomitantly facilitating N1 release from Nucb2.
核蛋白结合蛋白 2（Nucb2）和 nesfatin-1（N1）是广泛分布的激素，它们调节着从能量平衡到致癌作用等多种生理过程。然而，Nucb2 蛋白水解加工的第二种产物 nesfatin-2（N2）的作用仍不明确。为了阐明 nesfatin 之间的结构与功能关系，我们研究了鸡和人同源物 N1 以及由 N1 和 N2 头尾相连组成的 Nucb2 片段（N1/2）的特性。
我们的研究结果表明，锌（II）感应在鸡和人类物种中是保守的。然而，这里呈现的数据揭示了分析肽分子特征的显著差异，特别是在锌（II）存在的情况下。我们证明了锌（II）对 N1 和 N1/2 的 M30 区域（关键的厌食核心）具有双面影响。在 N1 同源物中，锌（II）结合导致 M30 区域的隐藏，这是由无序到有序的转变和淀粉样折叠的采用驱动的。相比之下，在 N1/2 分子中，锌（II）结合导致 M30 区域的暴露和失稳，导致 N1/2 分子中前激素转化酶识别区域的强烈暴露。
总之，我们发现鸡和人 N1 之间的锌（II）结合是保守的。然而，尽管鸡和人 N1 具有高度同源性，但它们与锌（II）的相互作用模式似乎不同。此外，锌（II）结合可能对于通过时空上阻碍 N1 的厌食 M30 核心并同时促进 N1 从 Nucb2 释放来调节 nesfatin 的功能是必要的。
