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1.
Mol Cell ; 84(10): 1995-2005.e7, 2024 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-38614096

RESUMO

Cytokines regulate immune responses by binding to cell surface receptors, including the common subunit beta (ßc), which mediates signaling for GM-CSF, IL-3, and IL-5. Despite known roles in inflammation, the structural basis of IL-5 receptor activation remains unclear. We present the cryo-EM structure of the human IL-5 ternary receptor complex, revealing architectural principles for IL-5, GM-CSF, and IL-3. In mammalian cell culture, single-molecule imaging confirms hexameric IL-5 complex formation on cell surfaces. Engineered chimeric receptors show that IL-5 signaling, as well as IL-3 and GM-CSF, can occur through receptor heterodimerization, obviating the need for higher-order assemblies of ßc dimers. These findings provide insights into IL-5 and ßc receptor family signaling mechanisms, aiding in the development of therapies for diseases involving deranged ßc signaling.


Assuntos
Microscopia Crioeletrônica , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Interleucina-3 , Multimerização Proteica , Receptores de Interleucina-5 , Transdução de Sinais , Humanos , Sítios de Ligação , Subunidade beta Comum dos Receptores de Citocinas/metabolismo , Subunidade beta Comum dos Receptores de Citocinas/genética , Subunidade beta Comum dos Receptores de Citocinas/química , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/química , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Células HEK293 , Interleucina-3/metabolismo , Interleucina-3/química , Interleucina-3/genética , Interleucina-5/metabolismo , Modelos Moleculares , Ligação Proteica , Receptores de Interleucina-5/metabolismo , Receptores de Interleucina-5/genética , Receptores de Interleucina-5/química , Imagem Individual de Molécula , Relação Estrutura-Atividade
2.
Nature ; 609(7927): 622-629, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35863378

RESUMO

The IL-17 family of cytokines and receptors have central roles in host defence against infection and development of inflammatory diseases1. The compositions and structures of functional IL-17 family ligand-receptor signalling assemblies remain unclear. IL-17E (also known as IL-25) is a key regulator of type 2 immune responses and driver of inflammatory diseases, such as allergic asthma, and requires both IL-17 receptor A (IL-17RA) and IL-17RB to elicit functional responses2. Here we studied IL-25-IL-17RB binary and IL-25-IL-17RB-IL-17RA ternary complexes using a combination of cryo-electron microscopy, single-molecule imaging and cell-based signalling approaches. The IL-25-IL-17RB-IL-17RA ternary signalling assembly is a C2-symmetric complex in which the IL-25-IL-17RB homodimer is flanked by two 'wing-like' IL-17RA co-receptors through a 'tip-to-tip' geometry that is the key receptor-receptor interaction required for initiation of signal transduction. IL-25 interacts solely with IL-17RB to allosterically promote the formation of the IL-17RB-IL-17RA tip-to-tip interface. The resulting large separation between the receptors at the membrane-proximal level may reflect proximity constraints imposed by the intracellular domains for signalling. Cryo-electron microscopy structures of IL-17A-IL-17RA and IL-17A-IL-17RA-IL-17RC complexes reveal that this tip-to-tip architecture is a key organizing principle of the IL-17 receptor family. Furthermore, these studies reveal dual actions for IL-17RA sharing among IL-17 cytokine complexes, by either directly engaging IL-17 cytokines or alternatively functioning as a co-receptor.


Assuntos
Interleucina-17 , Receptores de Interleucina-17 , Microscopia Crioeletrônica , Interleucina-17/química , Interleucina-17/metabolismo , Ligantes , Domínios Proteicos , Multimerização Proteica , Receptores de Interleucina-17/química , Receptores de Interleucina-17/metabolismo , Receptores de Interleucina-17/ultraestrutura , Transdução de Sinais , Imagem Individual de Molécula
3.
Nat Struct Mol Biol ; 30(4): 551-563, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36959263

RESUMO

The adipokine Leptin activates its receptor LEP-R in the hypothalamus to regulate body weight and exerts additional pleiotropic functions in immunity, fertility and cancer. However, the structure and mechanism of Leptin-mediated LEP-R assemblies has remained unclear. Intriguingly, the signaling-competent isoform of LEP-R is only lowly abundant amid several inactive short LEP-R isoforms contributing to a mechanistic conundrum. Here we show by X-ray crystallography and cryo-EM that, in contrast to long-standing paradigms, Leptin induces type I cytokine receptor assemblies featuring 3:3 stoichiometry and demonstrate such Leptin-induced trimerization of LEP-R on living cells via single-molecule microscopy. In mediating these assemblies, Leptin undergoes drastic restructuring that activates its site III for binding to the Ig domain of an adjacent LEP-R. These interactions are abolished by mutations linked to obesity. Collectively, our study provides the structural and mechanistic framework for how evolutionarily conserved Leptin:LEP-R assemblies with 3:3 stoichiometry can engage distinct LEP-R isoforms to achieve signaling.


Assuntos
Adipocinas , Leptina , Leptina/genética , Leptina/metabolismo , Leptina/farmacologia , Isoformas de Proteínas/genética , Transdução de Sinais
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