Aplysia allatotropin-related peptide and its newly identified d-amino acid-containing epimer both activate a receptor and a neuronal target
Aplysia allatotropin-related peptide and its newly identified d-amino acid-containing epimer both activate a receptor and a neuronal target
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海兔促尿素相关肽及其新鉴定的含 d-氨基酸差向异构体均能激活受体和神经元靶标
DOI：
10.1074/jbc.ra118.004367
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发表时间：
2018-10-26
影响因子：
4.8
通讯作者：
Sweedler, Jonathan V.
中科院分区：
文献类型：
--
作者：
Checco, James W.;Zhang, Guo;Sweedler, Jonathan V.
l-至d-残基异构化是存在于来自几种动物的神经肽、肽激素和肽毒素中的翻译后修饰（PTM）。在大多数情况下，d-残基对于所得含d-氨基酸的肽（DAACP）的生物学功能至关重要。在这里，我们提供了一个天然神经肽的例子，其中DAACP及其全-l-氨基酸差向异构体在其新鉴定的体外受体和与摄食行为相关的神经元靶点上都是活性的。基于与来自锥螺毒液的已知DAACP的序列相似性，我们假设来自神经科学模式生物加利福尼亚阿托西亚的一种神经肽--促生长素相关肽（ATRP）可能在阿托西亚中枢神经系统中形成多种非对映异构体。我们确定ATRP作为含d-氨基酸的肽（d2-ATRP）存在，并确定了一种特异性G蛋白偶联受体作为ATRP受体。有趣的是，与许多先前报道的DAACP及其全-I-残基类似物不同，I-ATRP和d2-ATRP都是该受体的有效激动剂，并且在电生理实验中具有活性。最后，d2-ATRP是更稳定的比它的所有-l-残基对应物在失活的血浆中，这表明在ATRP的情况下，l-d-残基异构化的主要作用可能是保护该肽从细胞外空间中的氨肽酶活性。我们的研究结果表明，l-到d-残基异构化可以发生，甚至在所有的l-残基肽与已知的生物活性，在某些情况下，这种PTM可能有助于调节肽信号的寿命在细胞外空间，而不是在同源受体的活性。
l- to d-residue isomerization is a post-translational modification (PTM) present in neuropeptides, peptide hormones, and peptide toxins from several animals. In most cases, the d-residue is critical for the biological function of the resulting d-amino acid-containing peptide (DAACP). Here, we provide an example in native neuropeptides in which the DAACP and its all-l-amino acid epimer are both active at their newly identified receptor in vitro and at a neuronal target associated with feeding behavior. On the basis of sequence similarity to a known DAACP from cone snail venom, we hypothesized that allatotropin-related peptide (ATRP), a neuropeptide from the neuroscience model organism Aplysia californica, may form multiple diastereomers in the Aplysia central nervous system. We determined that ATRP exists as a d-amino acid-containing peptide (d2-ATRP) and identified a specific G protein-coupled receptor as an ATRP receptor. Interestingly, unlike many previously reported DAACPs and their all-l-residue analogs, both l-ATRP and d2-ATRP were potent agonists of this receptor and active in electrophysiological experiments. Finally, d2-ATRP was much more stable than its all-l-residue counterpart in Aplysia plasma, suggesting that in the case of ATRP, the primary role of the l- to d-residue isomerization may be to protect this peptide from aminopeptidase activity in the extracellular space. Our results indicate that l- to d-residue isomerization can occur even in an all-l-residue peptide with a known biological activity and that in some cases, this PTM may help modulate peptide signal lifetime in the extracellular space rather than activity at the cognate receptor.