Emerging Structure–Function Paradigm of Endocrine FGFs in Metabolic Diseases

eFGFs are key regulators of metabolic homeostasis of lipids, glucose, energy, bile acids, and minerals. Alterations in the components of eFGF signaling complex underlie a myriad of metabolic diseases. The recently resolved crystal structures of eFGF signaling complexes open a new door for structure-based drug design. Klotho (or betaKlotho), through its pseudo-catalytic pocket and receptor-binding arm, serves as a scaffold to tether eFGF to FGFR. With an FDA-approved FGF23-based drug in the market, several other eFGF analogs and FGFR–KL/KLB agonists are on the horizon for various metabolic diseases. Endocrine fibroblast growth factors (eFGFs) control pathways that are crucial for maintaining metabolic homeostasis of lipids, glucose, energy, bile acids, and minerals. Unlike the heparin-binding paracrine FGFs, eFGFs require a unique Klotho family protein to form a productive triad complex, but the structural and mechanistical details of this complex have remained obscure since the beginning of the eFGF field. However, recent breakthroughs in resolving the 3D structures of eFGF signaling complexes have now unveiled the atomic details of multivalent interactions among eFGF, FGFR, and Klotho. We provide here a timely review on the architecture and the structure–function relationships of these complexes, and highlight how the structural knowledge opens a new door to structure-based drug design against a repertoire of eFGF-associated metabolic diseases. Endocrine fibroblast growth factors (eFGFs) control pathways that are crucial for maintaining metabolic homeostasis of lipids, glucose, energy, bile acids, and minerals. Unlike the heparin-binding paracrine FGFs, eFGFs require a unique Klotho family protein to form a productive triad complex, but the structural and mechanistical details of this complex have remained obscure since the beginning of the eFGF field. However, recent breakthroughs in resolving the 3D structures of eFGF signaling complexes have now unveiled the atomic details of multivalent interactions among eFGF, FGFR, and Klotho. We provide here a timely review on the architecture and the structure–function relationships of these complexes, and highlight how the structural knowledge opens a new door to structure-based drug design against a repertoire of eFGF-associated metabolic diseases. also called adipocyte browning. Beigeing is a transitory process in which the white adipocytes express ‘thermogenes’ typically associated with brown fat in response to thermogenic stimuli, resulting in the induction and enhancement of thermogenesis in the white fat. The resulting adipocytes are called beige or brite cells, and these enhance energy expenditure by catabolizing lipids stored within the adipose tissue. a native or mimetic molecule or substance that binds to a receptor and activates it to initiate a signaling cascade, resulting in a biological response. also called Klotho Beta, KLB is a homolog of KL but interacts with FGFRs and FGF19/FGF21. members of the FGF family, which include FGF1–10, 16–18, 20, and 22, that have appreciable affinity for extracellular matrix heparan sulfate (HS) and act through the FGFRs in the presence of cofactor HS to promote cell proliferation and population growth in an autocrine or paracrine fashion. a clinical condition in which bile acids are retained instead of being normally excreted from the liver into duodenum, resulting in pruritus, jaundice, pale stool, and/or dark urine. A decrease in bile flow can be caused by an impaired secretion by hepatocytes or an obstruction of intra- or extrahepatic bile ducts. an FGF subfamily with three members, FGF19, 21, and 23, which lack a classic heparin-binding domain, and thus lack extracellular matrix retention. They act through the circulation and target the signaling complexes of FGFRs and Klotho/betaKlotho to affect metabolic homeostasis of distal target tissues and organs. a family of polypeptides that have an atypical β-trefoil core of about 120 amino acids in length, with divergent N- and C-termini, and that signal through the transmembrane receptor tyrosine kinases, the fibroblast growth factor receptors (FGFRs). There are 22 FGF members in humans. a family of transmembrane proteins with two or three immunoglobulin (Ig)-like extracellular FGF-binding domains and two tandem intracellular signal-relay tyrosine kinase domains that are encoded by four genes in humans (FGFR1–4), where subtypes IIIb and IIIc are the main isoforms, which differ in ligand specificity and tissue distribution. a dimeric complex at the cell surface in which each symmetrical unit is composed of a canonic FGF ligand, an HS chain, and a FGFR, or an endocrine FGF (eFGF), a Klotho protein, an HS chain, and a FGFR. The formation of this dimer complex in the extracellular milieu changes the proximity and topology of the two intracellular kinase subunits, leading to their transphosphorylation and downstream signal relay. also called the G-box, is a stretch of amino acids with a conserved XBXGXXBBGXXS/T (B, basic amino acid; G, glycine; S/T, serine/threonine) motif located between β-strands 10 and 12 in the central core of canonical FGFs. It overlaps with the heparin-binding domain, and therefore contributes to the interaction with both heparan sulfate and FGFR. However, the lack of conservation in this motif and truncation in the β10–β12 region generate a defective heparin-binding domain with steric hindrance in the endocrine FGFs. a type of highly sulfated and negatively charged linear glycosaminoglycan that is composed of glucosamine and uronic acid disaccharide repeats with a varying degree of modifications. HS is found at the cell surface and in the extracellular matrix, where it interacts with a plethora of proteins. a linear glycosaminoglycan structurally similar to HS, but with a higher degree of sulfation, and is produced and stored intracellularly by basophils and mast cells. a surface area of a protein – such as the FGF or FGFR – that makes contact with a heparin or HS through electrostatic and hydrogen bonds. This surface area is usually rich in basic amino acids and adopts a shallow groove topology. also called alphaKlotho or Klotho alpha, KL is a single-spanning transmembrane protein with a short intracellular C tail and two large tandem extracellular homologous modules with sequence homology and phylogeny to the family of β-glucosidases of bacteria and plants as well as to the mammalian lactase glycosylceramidase. It interacts with endocrine FGF23 and FGFRs via the pseudo-catalytic pocket and the long receptor-binding arm, respectively, and serves as an obligate coreceptor of eFGF signaling complex rather than as an active glycolytic enzyme. a relatively stable state of equilibrium in the metabolism of nutrients, substrates, intermediates and energy in a cell, organ, or organism that is independent of external changes: the condition for optimal functioning of the cell, organ, or organism. also known as meta-inflammation, this is a low-grade, chronic inflammation orchestrated by cells in metabolically active tissue in response to excess nutrient, energy overload, or metabolic disturbance. an analogous substrate-binding enzyme pocket formed between the two tandem family I glycosidase-like modules in the extracellular portion of Klotho or betaKlotho. Owing to the lack of one of the two catalytic Glu resides in each of the two modules, this pocket is able to bind to C-terminal sugar-mimicking motif of eFGF but is devoid of enzymatic activity. a long rod- or arm-like 3D structure formed by a stretch of N-terminal sequence in the KL-m2 module of KL or KLB, which protrudes from the KL-m2 barrel core and latches onto a hydrophobic groove on the surface of the D3 domain of FGFR1. a mode of futile energy expenditure in which chemical energy in substrates is converted to heat, which is subsequently dissipated into the surroundings. This process is usually achieved in mitochondria of brown adipose tissue (BAT) and beige adipocytes in white adipose tissue (WAT) through mitochondrial oxidative metabolism and UCP1-dependent uncoupling of ATP production from heat generation, resulting in a rise of body temperature and heat dissipation into the surroundings. a 3D arrangement of different structural elements in proteins characterized by 12 β-strands folded into three similar β–β–β-loop–β (trefoil) units, which then form a six-stranded barrel capped by a triangular hairpin triplet with pseudo-threefold symmetry.