Despite recent breakthroughs in G protein-coupled receptor (GPCR) structure characterization, there is only sparse data on how GPCRs recognize larger peptide ligands. Here, we integrate nuclear magnetic resonance (NMR) spectroscopy, molecular modeling, and double-cycle mutagenesis studies to obtain a structural model of the peptide hormone neuropeptide Y (NPY), bound to its human G protein-coupled Y2 receptor (Y2R). Solid-state NMR measurements of specifically isotope-labeled NPY in complex with in vitro folded Y2R reconstituted into phospholipid bicelles provide the bioactive structure of the peptide. Guided by solution NMR experiments, we find that the ligand is tethered to the second extracellular loop by hydrophobic contacts. The C-terminal α-helix of NPY, which is formed in membrane environment in the absence of the receptor, is unwound starting at T32 to provide optimal contacts in a deep binding pocket within the transmembrane bundle of the Y2R.
Chemerin is an immunomodulating factor secreted predominantly by adipose tissue and skin. Processed by a variety of proteases linked to inflammation, it activates the G-protein coupled receptor chemokine-like receptor 1 (CMKLR1) and induces chemotaxis in natural killer cells, macrophages, and immature dendritic cells. Recent developments revealed the role of the nonsignaling chemerin receptor C-C chemokine receptor-like 2 (CCRL2) in inflammation. Besides further research establishing its link to inflammatory skin conditions such as psoriasis, functions in healthy skin have also been reported. Here, the current understanding of chemerin processing, signaling and physiological function has been summarized, focusing on the regulation of its activity, its different receptors and its controversially discussed role in diseases.
The excessive accumulation of adipose tissue in obesity is associated with multiple inflammatory dermatological diseases. Chemerin, a chemoattractant adipokine, dependent on proteolytical activation, is highly expressed in skin. Different proteases have been reported to activate prochemerin, but none is inherently expressed in human skin. In the present study, we identified a tissue-specific protease and investigated the underlying mechanism of activation at the molecular level. We characterized human KLK7 (kallikrein 7) as a prochemerin processing protease in vitro converting prochemerin into active chemerinF(156). The activating truncation by the protease might trigger a structural rearrangement leading to an increased affinity of chemerin to CMKLR1 (chemokine-like receptor 1). Molecular modelling and experimental data suggest an underlying ionic interaction in prochemerin C-terminal domains. These findings provide a general molecular basis for the necessity of C-terminal processing of prochemerin. Moreover, immunohistochemistry was used to investigate prochemerin, KLK7 and the recently identified KLK7 inhibitor vaspin expression in human skin biopsies, and distinct co-localization in psoriatic biopsies was observed. On the basis of these results, it is hypothesized that KLK7 activity may contribute to the development of psoriatic lesions as a consequence of excessive chemerin activation and impaired protease activity regulation by vaspin. Therefore this interaction represents an interesting target for psoriasis therapy and treatment of other obesity-related diseases.
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