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Structural insights into the assembly of large oligomeric signalosomes in the Toll-like receptor-interleukin-1 receptor superfamily.

ABSTRACT: The Toll-like receptor (TLR)-interleukin 1 receptor (IL-1R) superfamily plays fundamentally important roles in innate immune and inflammatory responses. Structural studies have begun to show that upon ligand stimulation, TLRs and IL-1Rs assemble large oligomeric intracellular signaling complexes, or "signalosomes," to induce the activation of kinases and E3 ubiquitin ligases, leading eventually to the activation of the transcription factors that are responsible for the expression of genes whose products mediate immune and inflammatory responses. The different scaffolds identified by these structural studies provide a molecular foundation for understanding the formation of microscopically visible signaling clusters that have long been known to cell biologists. Here, we illustrate the potential mechanisms of step-by-step assembly from the membrane-proximal interactions to the more downstream events. Formation of large oligomeric signalosomes may help to establish a digital threshold response in TLR and IL-1R signaling.

SUBMITTER: Ferrao R

PROVIDER: S-EPMC3568634 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Structural insights into the assembly of large oligomeric signalosomes in the Toll-like receptor-interleukin-1 receptor superfamily.

Ferrao Ryan R Li Jixi J Bergamin Elisa E Wu Hao H

Science signaling 20120529 226

The Toll-like receptor (TLR)-interleukin 1 receptor (IL-1R) superfamily plays fundamentally important roles in innate immune and inflammatory responses. Structural studies have begun to show that upon ligand stimulation, TLRs and IL-1Rs assemble large oligomeric intracellular signaling complexes, or "signalosomes," to induce the activation of kinases and E3 ubiquitin ligases, leading eventually to the activation of the transcription factors that are responsible for the expression of genes whose ...[more]

PMID: 22649099

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Project description:Centrosomal P4.1-associated protein (CPAP) is a cell cycle regulated protein fundamental for centrosome assembly and centriole elongation. In humans, the region between residues 897-1338 of CPAP mediates interactions with other proteins and includes a homodimerization domain. CPAP mutations cause primary autosomal recessive microcephaly and Seckel syndrome. Despite of the biological/clinical relevance of CPAP, its mechanistic behavior remains unclear and its C-terminus (the G-box/TCP domain) is the only part whose structure has been solved. This situation is perhaps due in part to the challenges that represent obtaining the protein in a soluble, homogeneous state for structural studies. Our work constitutes a systematic structural analysis on multiple oligomers of HsCPAP897-1338, using single-particle electron microscopy (EM) of negatively stained (NS) samples. Based on image classification into clearly different regular 3D maps (putatively corresponding to dimers and tetramers) and direct observation of individual images representing other complexes of HsCPAP897-1338 (i.e., putative flexible monomers and higher-order multimers), we report a dynamic oligomeric behavior of this protein, where different homo-oligomers coexist in variable proportions. We propose that dimerization of the putative homodimer forms a putative tetramer which could be the structural unit for the scaffold that either tethers the pericentriolar material to centrioles or promotes procentriole elongation. A coarse fitting of atomic models into the NS 3D maps at resolutions around 20 Å is performed only to complement our experimental data, allowing us to hypothesize on the oligomeric composition of the different complexes. In this way, the current EM work represents an initial step toward the structural characterization of different oligomers of CPAP, suggesting further insights to understand how this protein works, contributing to the elucidation of control mechanisms for centriole biogenesis.

Dataset Information

Structural insights into the assembly of large oligomeric signalosomes in the Toll-like receptor-interleukin-1 receptor superfamily.

Publications

Structural insights into the assembly of large oligomeric signalosomes in the Toll-like receptor-interleukin-1 receptor superfamily.

Similar Datasets

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