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Cryo-EM structure of human CMKLR1-Gi complex bound to chemerin
Structural highlights
FunctionCML1_HUMAN Receptor for the chemoattractant adipokine chemerin/RARRES2 and for the omega-3 fatty acid derived molecule resolvin E1. Interaction with RARRES2 initiates activation of G proteins G(i)/G(o) and beta-arrestin pathways inducing cellular responses via second messenger pathways such as intracellular calcium mobilization, phosphorylation of MAP kinases MAPK1/MAPK3 (ERK1/2), TYRO3, MAPK14/P38MAPK and PI3K leading to multifunctional effects, like reduction of immune responses, enhancing of adipogenesis and angionesis (PubMed:27716822). Resolvin E1 down-regulates cytokine production in macrophages by reducing the activation of MAPK1/3 (ERK1/2) and NF-kappa-B. Positively regulates adipogenesis and adipocyte metabolism.[1] [2] [3] [4] (Microbial infection) Acts as a coreceptor for several SIV strains (SIVMAC316, SIVMAC239, SIVMACL7E-FR and SIVSM62A), as well as a primary HIV-1 strain (92UG024-2).[5] Publication Abstract from PubMedChemerin, a chemotactic adipokine, plays essential roles in adipogenesis and inflammation. Serum chemerin concentration is closely associated with obesity and metabolism disorders. The mature form of chemerin (residues 21-157) acts primarily through chemerin receptor 1 (CMKLR1) for transmembrane signaling. As a result, CMKLR1 serves as a promising target for therapeutic intervention of immunometabolic diseases such as diabetes and multiple sclerosis. Here, we present a high-resolution cryo-EM structure of CMKLR1-Gi signaling complex bound to biologically active full-length chemerin. The mature chemerin shows binding features distinct from its C-terminal nonapeptide including interaction with both the extracellular loops (ECLs) and the N-terminus of CMKLR1. Combining results from functional assays, our studies demonstrate that chemerin interacts with CMKLR1 in a "two-site" mode similar to chemokine-chemokine receptor interactions, but acting as a "reverse chemokine" by inserting its C-terminus instead of the N-terminus as in the case of chemokines into the transmembrane binding pocket of CMKLR1. These structural insights are expected to help develop synthetic analogs with therapeutic potential. Structural basis for full-length chemerin recognition and signaling through chemerin receptor 1.,Liu A, Liu Y, Wang J, Ye RD Commun Biol. 2024 Nov 30;7(1):1598. doi: 10.1038/s42003-024-07228-9. PMID:39616240[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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