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The role of protein-protein interactions in toll-like receptor function

The role of protein-protein interactions in toll-like receptor function
The role of protein-protein interactions in toll-like receptor function
As part of the innate immune system, the Toll-like receptors (TLRs) represent key players in the first line of defense against invading foreign pathogens, and are also major targets for therapeutic immunomodulation. TLRs are type I transmembrane proteins composed of an ectodomain responsible for ligand binding, a single-pass transmembrane domain, and a cytoplasmic Toll/Interleukin-1 receptor (TIR) signaling domain. The ectodomains of TLRs are specialized for recognizing a wide variety of pathogen-associated molecular patterns, ranging from lipids and lipopeptides to proteins and nucleic acid fragments. The members of the TLR family are highly conserved and their ectodomains are composed of characteristic, solenoidal leucine-rich repeats (LRRs). Upon ligand binding, these rigid LRR scaffolds dimerize (or re-organize in the case of pre-formed dimers) to bring together their carboxy-terminal transmembrane and TIR domains. The latter are proposed to act as a platform for recruitment of adaptor proteins and formation of higher-order complexes, resulting in propagation of downstream signaling cascades. In this review, we discuss the protein-protein interactions critical for formation and stability of productive, ligand-bound TLR complexes. In particular, we focus on the large body of high-resolution crystallographic data now available for the ectodomains of homo- and heterodimeric TLR complexes, as well as inhibitory TLR-like receptors, and also consider computational approaches that can facilitate our understanding of the ligand-induced conformational changes associated with TLR function. We also briefly consider what is known about the protein-protein interactions involved in both TLR transmembrane domain assembly and TIR-mediated signaling complex formation in light of recent structural and biochemical data.
innate immunity, leucine-rich repeats, pathogen associated molecular patterns, signaling complex formation, toll-like receptors, transmembrane domain assembly
0079-6107
1-12
Berglund, Nils
01f23146-6b2d-4c6f-a090-85e6dad99ec3
Kargas, Vasileios
4c3b7616-e8a6-4fef-aba7-d9a2e45766d0
Ortiz-Suarez, Maite L.
628671e0-e605-4a32-83de-35d16993591e
Bond, Peter J.
08f46940-85e8-44c4-a368-d94342a10fd6
Berglund, Nils
01f23146-6b2d-4c6f-a090-85e6dad99ec3
Kargas, Vasileios
4c3b7616-e8a6-4fef-aba7-d9a2e45766d0
Ortiz-Suarez, Maite L.
628671e0-e605-4a32-83de-35d16993591e
Bond, Peter J.
08f46940-85e8-44c4-a368-d94342a10fd6

Berglund, Nils, Kargas, Vasileios, Ortiz-Suarez, Maite L. and Bond, Peter J. (2015) The role of protein-protein interactions in toll-like receptor function. Progress in Biophysics and Molecular Biology, 1-12. (doi:10.1016/j.pbiomolbio.2015.06.021). (PMID:26144017)

Record type: Article

Abstract

As part of the innate immune system, the Toll-like receptors (TLRs) represent key players in the first line of defense against invading foreign pathogens, and are also major targets for therapeutic immunomodulation. TLRs are type I transmembrane proteins composed of an ectodomain responsible for ligand binding, a single-pass transmembrane domain, and a cytoplasmic Toll/Interleukin-1 receptor (TIR) signaling domain. The ectodomains of TLRs are specialized for recognizing a wide variety of pathogen-associated molecular patterns, ranging from lipids and lipopeptides to proteins and nucleic acid fragments. The members of the TLR family are highly conserved and their ectodomains are composed of characteristic, solenoidal leucine-rich repeats (LRRs). Upon ligand binding, these rigid LRR scaffolds dimerize (or re-organize in the case of pre-formed dimers) to bring together their carboxy-terminal transmembrane and TIR domains. The latter are proposed to act as a platform for recruitment of adaptor proteins and formation of higher-order complexes, resulting in propagation of downstream signaling cascades. In this review, we discuss the protein-protein interactions critical for formation and stability of productive, ligand-bound TLR complexes. In particular, we focus on the large body of high-resolution crystallographic data now available for the ectodomains of homo- and heterodimeric TLR complexes, as well as inhibitory TLR-like receptors, and also consider computational approaches that can facilitate our understanding of the ligand-induced conformational changes associated with TLR function. We also briefly consider what is known about the protein-protein interactions involved in both TLR transmembrane domain assembly and TIR-mediated signaling complex formation in light of recent structural and biochemical data.

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Accepted/In Press date: 30 June 2015
e-pub ahead of print date: 2 July 2015
Keywords: innate immunity, leucine-rich repeats, pathogen associated molecular patterns, signaling complex formation, toll-like receptors, transmembrane domain assembly
Organisations: Chemistry

Identifiers

Local EPrints ID: 378959
URI: https://eprints.soton.ac.uk/id/eprint/378959
ISSN: 0079-6107
PURE UUID: 9727e7e6-1ab4-4eff-a881-5d5c4bd40d0a

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Date deposited: 15 Jul 2015 08:45
Last modified: 17 Jul 2017 20:48

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