Fibroblast growth factors (FGFs) are cell-signaling proteins with diverse functions in cell development, repair, and metabolism. The human FGF family consists of 22 structurally related members, which can be classified into three separate groups based on their action of mechanisms, namely: intracrine, paracrine/autocrine, and endocrine FGF subfamilies. FGF19, FGF21, and FGF23 belong to the hormone-like/endocrine FGF subfamily. These endocrine FGFs are mainly associated with the regulation of cell metabolic activities such as homeostasis of lipids, glucose, energy, bile acids, and minerals (phosphate/active vitamin D). Endocrine FGFs function through a unique protein family called klotho. Two members of this family, α-klotho, or β-klotho, act as main cofactors which can scaffold to tether FGF19/21/23 to their receptor(s) (FGFRs) to form an active complex. There are ongoing studies pertaining to the structure and mechanism of these individual ternary complexes. These studies aim to provide potential insights into the physiological and pathophysiological roles and therapeutic strategies for metabolic diseases. Herein, we provide a comprehensive review of the history, structure–function relationship(s), downstream signaling, physiological roles, and future perspectives on endocrine FGFs.
Human Fibroblast growth factor 1 (hFGF1) is a member of FGF1 subfamily which play significant biological roles, including cell proliferation, cell differentiation, and wound healing. Under physiological temperatures, hFGF1 has low thermodynamic stability and susceptible to the action of proteases. Circular dichroism, fluorescence spectroscopy, and other related studies reveal that reversal of charge on R136 by acidic amino acids (Glu) drastically increases the enzymatic resistance to thrombin, thermal stability, and cell proliferation activity of the growth factor. Interestingly, introduction of R136D mutation shows that the protein stability and cell proliferation activity is similar to the wild‐type protein. Microsecond molecular dynamics studies suggest that length of the side chain of acidic amino acid at position 136 is critical to confer stability to the protein. Detailed analysis of the results will be presented.
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