The role of protein–protein interactions in Toll-like receptor function

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 TIRmediated signaling complex formation in light of recent structural and biochemical data.

An immunoinformatic approach driven by experimental proteomics: in silico design of a subunit candidate vaccine targeting secretory proteins of Leishmania donovani amastigotes

“…It is thus possible that a change in the interpolated charge difference between pre-dock and post-dock TLR4 interface could have contributed to the bonding rearrangement between TLR4 ECDs. Notably, this rearrangement also involved participation of other critical histidine (His431, His555) residues at the TLR4-TLR4* interface [80] unlike the unbound structure (Additional file 8: Figure S5). Overall, these events are congruent with non-canonical TLR4 activation model mediated by microbial peptides, metals and cationic lipid nano-carriers, which are suggested to not confer canonical interaction with other monomers but to induce bond rearrangement among receptor monomers upon interaction [74][75][76][77].…”

Energetics and Dynamics Across the Bcl-2-Regulated Apoptotic Pathway Reveal Distinct Evolutionary Determinants of Specificity and Affinity

“…Indeed, instances 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 where a pool of structurally similar small molecules/peptides/proteins bind a well defined region on a set of structurally similar protein partners are found in all domains of life and physiological pathways (Friedman & Hughes, 2001). Our hypothesis may provide an attractive framework to investigate in a similar manner physiologically and therapeutically relevant systems, e.g., the bZIP transcription factors (Nair & Burley, 2003) and EGF receptors (Arkhipov et al, 2014), which have been implicated in malignant cellular proliferation; histidine kinase -response regulator protein interactions, central to signal transduction in bacterial cells (Casino et al, 2009); Toll-like receptors (Berglund et al, 2015) and MHC proteins (Patronov et al, 2012;Ivanov et al, 2012), both of which regulate immunity; and the E2 -E3 enzyme interaction, part of the ubiquitination pathway (Kar et al, 2012).…”

Positive and strongly relaxed purifying selection drive the evolution of repeats in proteins

“…Despite this strong evidence of the functionality and evolutionary conservation of repeats, repeat variation is also a known molecular driver of genetic disease3132, which indicates the importance of rapid change in repetitive regions of proteins. Furthermore, rapid evolution of protein repeats plays key roles in various aspects of immunity as exemplified by the leucine-rich repeats, which are the key structural components of innate immunity proteins, such as animal Toll-like receptors and plant disease resistance proteins, as well as adaptive immunity components in jawless vertebrates333435363738.…”