Researchers identify molecular signal recognition pathways in the neuropeptide system

Structures of three peptide-receptor complexes of the human NPY family. The peptide ligand is shown in orange (NPY) and red (PP), the receptors in blue and violet respectively, the interaction partner in the cell is a so-called G protein, shown in green. Top right: enlarged detailed image showing the bound structure and dynamics of NPY at Y1R and Y2R. Credit: Anette Kaiser, Leipzig University

The human body is composed of trillions of cells that are in constant communication. Receptor proteins on the cell surface play a significant part in this communication mechanism. Since they are frequently used as pharmacological targets, significant study has been conducted on them. There are frequently entire families of receptors. Since the signal messengers and receptors are quite similar, it is unclear how the signals are differentiated at the molecular level. Scientists from the Collaborative Research Centre 1423 at Leipzig University, the Hangzhou Institute for Advanced Study, and the Chinese Academy of Sciences in Shanghai have now determined the high-resolution structures of three naturally occurring signaling complexes for the neuropeptide Y (NPY) receptor family, shedding light on the subtle but essential differences. The scientists have now published their latest findings in Science Advances.

The NPY family consists of three similar peptide ligands, NPY, PP, and PYY, each of which has a distinct physiological role. Locally in the tissues, particularly the brain, and via the bloodstream, they operate as messengers. They attach to four distinct receptors (Y1R, Y2R, Y4R, and Y5R), with different combinations of peptide ligand and receptor happening in different situations: NPY in association with Y1R indicates hunger in the brain, whereas PP linked to Y4R communicates a strong satiety signal. Also of interest for current cancer therapeutics are NPY receptors. Due to the fact that breast cancer cells contain a large number of Y1R, NPY variants that selectively bind to this receptor could be employed to deliver medicines to these cells solely. On the other hand, Y2R is primarily found in breast tissueștiintifștiinștiiștiiștii It makes logical to avoid this in order to preserve the healthy tissue.

To be able to produce specific active compounds, it is crucial to understand the molecular architecture and underlying regulatory processes of these complexes. Professor Annette Beck-Sickinger and Dr. Anette Kaiser of Leipzig University conducted biochemical studies that shed more light on the complex mechanisms that bind the peptides to their receptors and supported the results of the structural studies. It was feasible to locate the crucial locations in the complex’s peptides and receptors.

The working groups have been conducting joint research in this sector for more than ten years, and these new findings are based on a substantial body of previous work. This increases the value of this joint publication, the third by the working groups. This is because a fresh test system revealed that the peptides utilize distinct “docking mechanisms,” which can result in distinct cell signals. In particular regions, the adaptability and mobility of the complexes also play a significant role. According to Professor Annette Beck-Sickinger “Thus, even in the bonded form, the peptide and receptor retain a portion of their flexibility. Current studies in CRC 1423 are investigating the causes and effects of this phenomenon, as well as the question of what additional factors influence the recognition between peptides and receptors.”

Further information: Tingting Tang et al, Receptor-specific recognition of NPY peptides revealed by structures of NPY receptors, Science Advances (2022). DOI: 10.1126/sciadv.abm1232

Journal information: Science Advances

Source: Leipzig University