Haack Michael, Beck-Sickinger Annette G
Institute of Biochemistry, Faculty of Bioscience, Pharmacy and Psychology, Leipzig University, Germany.
Chem Biol Drug Des. 2009 Jun;73(6):573-83. doi: 10.1111/j.1747-0285.2009.00823.x.
Despite a considerable sequence identity of the three mammalian hormones of the neuropeptide Y family, namely neuropeptide Y, peptide YY and pancreatic polypeptide, their structure in solution is described to be different. A so-called pancreatic polypeptide-fold has been identified for pancreatic polypeptide, whereas the structure of the N-terminal segment of neuropeptide Y is unknown. This element is important for the binding of neuropeptide Y to two of its relevant receptors, Y(1) and Y(5), but not to the Y(2) receptor subtype. In this study now, three doubly fluorescent-labeled analogs of neuropeptide Y have been synthesized that still bind to the Y(5) receptor with high affinity to investigate the conformation in solution and, for the first time, to probe the conformational changes upon binding of the ligand to its receptor in cell membrane preparations. The results obtained from the fluorescence resonance energy transfer investigations clearly show considerable differences in transfer efficiency that depend both on the solvent as well as on the peptide concentration. However, the studies do not support a pancreatic polypeptide-like folding of neuropeptide Y in the presence of membranes that express the human Y(5) receptor subtype.
尽管神经肽Y家族的三种哺乳动物激素，即神经肽Y、肽YY和胰多肽，具有相当高的序列同一性，但它们在溶液中的结构却有所不同。已确定胰多肽具有所谓的胰多肽折叠结构，而神经肽Y的N端片段结构尚不清楚。该元件对于神经肽Y与其两种相关受体Y(1)和Y(5)的结合很重要，但与Y(2)受体亚型的结合无关。在本研究中，现已合成了三种双荧光标记的神经肽Y类似物，它们仍能以高亲和力与Y(5)受体结合，以研究溶液中的构象，并首次探究配体与细胞膜制剂中受体结合时的构象变化。荧光共振能量转移研究所得结果清楚地表明，转移效率存在显著差异，这既取决于溶剂，也取决于肽浓度。然而，这些研究并不支持在表达人Y(5)受体亚型的膜存在的情况下，神经肽Y具有类似胰多肽的折叠结构。
