Soluble α-klotho-a fibroblast growth factor 23-independent hormone

Membranous α-Klotho (mKlotho) interacts with fibroblast growth factor receptor (FGFR) to form coreceptors for fibroblast growth factor 23 (FGF23). The ectodomain of mKlotho is shed (soluble Klotho; sKlotho) and functions as a circulating endocrine or local autocrine/paracrine factor. sKlotho exerts pleiotropic actions. Identification of membrane receptor(s) is essential for designating sKlotho to have “hormonal” function. Lipid rafts are membrane microdomain important in many cellular processes. Here, we review recent studies reporting that sialogangliosides of membrane lipid rafts serve as receptors for sKlotho. The X-ray crystal structure of sKlotho in ternary complex with FGFR and FGF23 has been solved. However, sKlotho binding to lipid rafts does not require FGF23 or FGFR. Computational studies including modeling, docking, and molecular dynamic simulations reveal that slight movement in the KL1 domain of sKlotho allows stable binding of the sialyllactose, headgroup of sialogangliosides. Thus, sKlotho satisfies the criteria to be an FGF23-independent hormone. Binding to lipid rafts may underlie the pleiotropic actions of sKlotho that seem to permeate all cells.