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1.
Nature ; 618(7966): 862-870, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37286607

RESUMO

α/ßKlotho coreceptors simultaneously engage fibroblast growth factor (FGF) hormones (FGF19, FGF21 and FGF23)1,2 and their cognate cell-surface FGF receptors (FGFR1-4) thereby stabilizing the endocrine FGF-FGFR complex3-6. However, these hormones still require heparan sulfate (HS) proteoglycan as an additional coreceptor to induce FGFR dimerization/activation and hence elicit their essential metabolic activities6. To reveal the molecular mechanism underpinning the coreceptor role of HS, we solved cryo-electron microscopy structures of three distinct 1:2:1:1 FGF23-FGFR-αKlotho-HS quaternary complexes featuring the 'c' splice isoforms of FGFR1 (FGFR1c), FGFR3 (FGFR3c) or FGFR4 as the receptor component. These structures, supported by cell-based receptor complementation and heterodimerization experiments, reveal that a single HS chain enables FGF23 and its primary FGFR within a 1:1:1 FGF23-FGFR-αKlotho ternary complex to jointly recruit a lone secondary FGFR molecule leading to asymmetric receptor dimerization and activation. However, αKlotho does not directly participate in recruiting the secondary receptor/dimerization. We also show that the asymmetric mode of receptor dimerization is applicable to paracrine FGFs that signal solely in an HS-dependent fashion. Our structural and biochemical data overturn the current symmetric FGFR dimerization paradigm and provide blueprints for rational discovery of modulators of FGF signalling2 as therapeutics for human metabolic diseases and cancer.


Assuntos
Fator de Crescimento de Fibroblastos 23 , Proteoglicanas de Heparan Sulfato , Hormônios , Receptores de Fatores de Crescimento de Fibroblastos , Transdução de Sinais , Humanos , Microscopia Crioeletrônica , Fator de Crescimento de Fibroblastos 23/química , Fator de Crescimento de Fibroblastos 23/metabolismo , Fator de Crescimento de Fibroblastos 23/ultraestrutura , Proteoglicanas de Heparan Sulfato/química , Proteoglicanas de Heparan Sulfato/metabolismo , Hormônios/química , Hormônios/metabolismo , Proteínas Klotho/química , Proteínas Klotho/metabolismo , Proteínas Klotho/ultraestrutura , Multimerização Proteica , Receptores de Fatores de Crescimento de Fibroblastos/química , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/ultraestrutura , Complexos Multiproteicos/química , Complexos Multiproteicos/metabolismo , Complexos Multiproteicos/ultraestrutura
2.
Nature ; 604(7905): 371-376, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35388216

RESUMO

The outer membrane of Gram-negative bacteria has an external leaflet that is largely composed of lipopolysaccharide, which provides a selective permeation barrier, particularly against antimicrobials1. The final and crucial step in the biosynthesis of lipopolysaccharide is the addition of a species-dependent O-antigen to the lipid A core oligosaccharide, which is catalysed by the O-antigen ligase WaaL2. Here we present structures of WaaL from Cupriavidus metallidurans, both in the apo state and in complex with its lipid carrier undecaprenyl pyrophosphate, determined by single-particle cryo-electron microscopy. The structures reveal that WaaL comprises 12 transmembrane helices and a predominantly α-helical periplasmic region, which we show contains many of the conserved residues that are required for catalysis. We observe a conserved fold within the GT-C family of glycosyltransferases and hypothesize that they have a common mechanism for shuttling the undecaprenyl-based carrier to and from the active site. The structures, combined with genetic, biochemical, bioinformatics and molecular dynamics simulation experiments, offer molecular details on how the ligands come in apposition, and allows us to propose a mechanistic model for catalysis. Together, our work provides a structural basis for lipopolysaccharide maturation in a member of the GT-C superfamily of glycosyltransferases.


Assuntos
Ligases , Lipopolissacarídeos , Antígenos O , Proteínas de Bactérias/química , Carbono-Oxigênio Ligases/química , Carbono-Oxigênio Ligases/genética , Microscopia Crioeletrônica , Glicosiltransferases , Bactérias Gram-Negativas , Lipopolissacarídeos/química , Lipopolissacarídeos/metabolismo
3.
Nat Rev Rheumatol ; 16(10): 547-564, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32807927

RESUMO

Regulated fibroblast growth factor (FGF) signalling is a prerequisite for the correct development and homeostasis of articular cartilage, as evidenced by the fact that aberrant FGF signalling contributes to the maldevelopment of joints and to the onset and progression of osteoarthritis. Of the four FGF receptors (FGFRs 1-4), FGFR1 and FGFR3 are strongly implicated in osteoarthritis, and FGFR1 antagonists, as well as agonists of FGFR3, have shown therapeutic efficacy in mouse models of spontaneous and surgically induced osteoarthritis. FGF18, a high affinity ligand for FGFR3, is the only FGF-based drug currently in clinical trials for osteoarthritis. This Review covers the latest advances in our understanding of the molecular mechanisms that regulate FGF signalling during normal joint development and in the pathogenesis of osteoarthritis. Strategies for FGF signalling-based treatment of osteoarthritis and for cartilage repair in animal models and clinical trials are also introduced. An improved understanding of FGF signalling from a structural biology perspective, and of its roles in skeletal development and diseases, could unlock new avenues for discovery of modulators of FGF signalling that can slow or stop the progression of osteoarthritis.


Assuntos
Cartilagem Articular/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Osteoartrite/metabolismo , Transdução de Sinais/fisiologia , Animais , Cartilagem Articular/patologia , Ensaios Clínicos como Assunto , Progressão da Doença , Homeostase/fisiologia , Humanos , Camundongos , Modelos Animais , Osteoartrite/fisiopatologia , Osteoartrite/terapia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/agonistas
4.
Front Genet ; 10: 102, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30809251

RESUMO

Mammalian fibroblast growth factor (FGF) signaling is intricately regulated via selective binding interactions between 18 FGF ligands and four FGF receptors (FGFR1-4), three of which (FGFR1-3) are expressed as either epithelial ("b") or mesenchymal ("c") splice isoforms. The FGF7 subfamily, consisting of FGF3, FGF7, FGF10, and FGF22, is unique among FGFs in that its members are secreted exclusively by the mesenchyme, and specifically activate the "b" isoforms of FGFR1 (FGFR1b) and FGFR2 (FGFR2b) present in the overlying epithelium. This unidirectional mesenchyme-to-epithelium signaling contributes to the development of essentially all organs, glands, and limbs. Structural analysis has shown that members of the FGF7 subfamily achieve their restricted specificity for FGFR1b/FGFR2b by engaging in specific contacts with two alternatively spliced loop regions in the immunoglobulin-like domain 3 (D3) of these receptors. Weak basal receptor-binding affinity further constrains the FGF7 subfamily's specificity for FGFR1b/2b. In this review, we elaborate on the structural determinants of FGF7 subfamily receptor-binding specificity, and discuss how affinity differences among the four members for the heparin sulfate (HS) co-receptor contribute to their disparate biological activities.

5.
F1000Res ; 72018.
Artigo em Inglês | MEDLINE | ID: mdl-29983915

RESUMO

Upon ligand engagement, the single-pass transmembrane receptor tyrosine kinases (RTKs) dimerize to transmit qualitatively and quantitatively different intracellular signals that alter the transcriptional landscape and thereby determine the cellular response. The molecular mechanisms underlying these fundamental events are not well understood. Considering recent insights into the structural biology of fibroblast growth factor signaling, we propose a threshold model for RTK signaling specificity in which quantitative differences in the strength/longevity of ligand-induced receptor dimers on the cell surface lead to quantitative differences in the phosphorylation of activation loop (A-loop) tyrosines as well as qualitative differences in the phosphorylation of tyrosines mediating substrate recruitment. In this model, quantitative differences on A-loop tyrosine phosphorylation result in gradations in kinase activation, leading to the generation of intracellular signals of varying amplitude/duration. In contrast, qualitative differences in the pattern of tyrosine phosphorylation on the receptor result in the recruitment/activation of distinct substrates/intracellular pathways. Commensurate with both the dynamics of the intracellular signal and the types of intracellular pathways activated, unique transcriptional signatures are established. Our model provides a framework for engineering clinically useful ligands that can tune receptor dimerization stability so as to bias the cellular transcriptome to achieve a desired cellular output.

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