RESUMEN
The Toll/interleukin-1 receptor (TIR) domains are key innate immune signalling modules. Here, we present the crystal structure of the TIR domain of human interleukin-1 receptor 10 (IL-1R10), also called interleukin 1 receptor accessory protein like 2. It is similar to that of IL-1R9 (IL-1RAPL1) but shows significant structural differences to those from Toll-like receptors (TLRs) and the adaptor proteins MyD88 adaptor-like protein (MAL) and MyD88. Interactions of TIR domains in their respective crystals and the higher-order assemblies (MAL and MyD88) reveal the presence of a common 'BCD surface', suggesting its functional significance. We also show that the TIR domains of IL-1R10 and IL-1R9 lack NADase activity, consistent with their structures. Our study provides a foundation for unravelling the functions of IL-1R9 and IL-1R10.
Asunto(s)
Proteína Accesoria del Receptor de Interleucina-1/química , Factor 88 de Diferenciación Mieloide , Receptores de Interleucina-1 , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Humanos , Glicoproteínas de Membrana/metabolismo , Estructura Terciaria de Proteína , Receptores de Interleucina-1/genética , Transducción de SeñalRESUMEN
TIR (Toll/interleukin-1 receptor/resistance protein) domains are cytoplasmic domains widely found in animals and plants, where they are essential components of the innate immune system. A key feature of TIR-domain function in signaling is weak and transient self-association and association with other TIR domains. An additional new role of TIR domains as catalytic enzymes has been established with the recent discovery of NAD+-nucleosidase activity by several TIR domains, mostly involved in cell-death pathways. Although self-association of TIR domains is necessary in both cases, the functional specificity of TIR domains is related in part to the nature of the TIR : TIR interactions in the respective signalosomes. Here, we review the well-studied TIR domain-containing proteins involved in eukaryotic immunity, focusing on the structures, interactions and their corresponding functional roles. Structurally, the signalosomes fall into two separate groups, the scaffold and enzyme TIR-domain assemblies, both of which feature open-ended complexes with two strands of TIR domains, but differ in the orientation of the two strands. We compare and contrast how TIR domains assemble and signal through distinct scaffolding and enzymatic roles, ultimately leading to distinct cellular innate-immunity and cell-death outcomes.
Asunto(s)
Dominios Proteicos/inmunología , Multimerización de Proteína/inmunología , Transducción de Señal/inmunología , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Alarminas/metabolismo , Secuencia de Aminoácidos , Animales , Resistencia a la Enfermedad/inmunología , Humanos , Moléculas de Patrón Molecular Asociado a Patógenos/metabolismo , Plantas , Dominios Proteicos/genética , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/metabolismo , Receptores de Interleucina-1/ultraestructura , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo , Receptores Toll-Like/ultraestructuraRESUMEN
TIR (Toll/interleukin-1 receptor/resistance protein) domains feature in animal, plant and bacterial proteins involved in innate immunity pathways and associated processes. They function through protein:protein interactions, in particular self-association and homotypic association with other TIR domains. Structures of TIR domains from all phyla have been determined, but common association modes have only emerged for plant and bacterial TIR domains, and not for mammalian TIR domains. Numerous attempts involving hybrid approaches, which have combined structural, computational, mutagenesis and biophysical data, have failed to converge onto common models of how these domains associate and function. We propose that the available data can be reconciled in the context of higher-order assembly formation, and that TIR domains function through signaling by cooperative assembly formation (SCAF).