The neuropeptide galanin adopts an irregular secondary structure.
The neuropeptide galanin adopts an irregular secondary structure.
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DOI：
10.1016/j.bbrc.2022.08.032
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发表时间：
2022-08
影响因子：
3.1
通讯作者：
Rachel E. Wilkinson;Katelyn N. Kraichely;Cecilia M Hendy;Lauren E. Buchanan;S. Parnham;Michael W. Giuliano
中科院分区：
文献类型：
--
作者：
Rachel E. Wilkinson;Katelyn N. Kraichely;Cecilia M Hendy;Lauren E. Buchanan;S. Parnham;Michael W. Giuliano
人甘丙肽是一种30个残基的神经肽，用于开发镇痛药、抗抑郁药和抗惊厥药。虽然我们小组和其他人以前的工作已经对甘丙肽的N-末端区域产生了重要的见解，但数据库中没有甘丙肽的现存结构包括其全长序列，其C-末端的功能仍然不明确。我们报告的NMR溶液结构的全长人类甘丙肽C-末端酰胺，确定从2D 1H-1H COSY，TOCSY和ROESY NMR数据。甘丙肽在其N末端采用不规则的螺旋结构，可能是几种卷曲状态的平均值。我们提出了一个肽的NMR结构，包括甘丙肽的C-末端作为一个独立的片段。全长甘丙肽的C-末端似乎间接地协助其N-末端内的疏水侧链的分子内缔合，当与先前研究的N-末端甘丙肽片段相比时，远程地使它们的位置刚性化。相比之下，甘丙肽的C-末端具有柔性，其特征在于在另外的动态骨架内具有两个1 + 2氢键键合的转角。肽的C-末端部分使其可溶，并且在预组织甘丙肽受体结合表位中起迄今未描述的生物物理作用。我们推测，信号肽，激素，也许内在无序的蛋白质的亲水性微区也可能发挥类似的功能。
Human galanin is a 30-residue neuropeptide targeted for development of analgesics, antidepressants, and anticonvulsants. While previous work from our group and others has already produced significant insights into galanin's N-terminal region, no extant structures of galanin in databases include its full-length sequence and the function of its C-terminus remains ambiguous. We report the NMR solution structure of full-length human galanin C-terminal amide, determined from 2D1H–1H COSY, TOCSY, and ROESY NMR data. Galanin adopts an irregular helical structure across its N-terminus, likely the average of several coiling states. We present the NMR structure of a peptide encompassing the C-terminus of galanin as a stand-alone fragment. The C-terminus of full-length galanin appears to indirectly assist the intramolecular association of hydrophobic sidechains within its N-terminus, remotely rigidifying their position when compared to previously studied N-terminal galanin fragments. By contrast, there is flexibility in the C-terminus of galanin, characterized by twoitoi+2hydrogen-bonded turns within an otherwise dynamic backbone. The C-terminal portion of the peptide renders it soluble, and plays a hitherto undescribed biophysical role in pre-organizing the galanin receptor binding epitope. We speculate that hydrophilic microdomains of signaling peptides, hormones, and perhaps intrinsically disordered proteins may also function similarly.