title: 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 TIR-mediated signaling complex formation in light of recent structural and biochemical data.
authors.affiliation: Bioinformatics Institute (A∗STAR), 30 Biopolis Str., #07-01 Matrix, 138671, Singapore; School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK.
authors.forename: Nils A
authors.initials: NA
authors.lastname: Berglund
authors.affiliation: Bioinformatics Institute (A∗STAR), 30 Biopolis Str., #07-01 Matrix, 138671, Singapore; Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Vasileios
authors.initials: V
authors.lastname: Kargas
authors.affiliation: Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Maite L
authors.initials: ML
authors.lastname: Ortiz-Suarez
authors.affiliation: Bioinformatics Institute (A∗STAR), 30 Biopolis Str., #07-01 Matrix, 138671, Singapore; National University of Singapore, Department of Biological Sciences, 14 Science Drive 4, 117543, Singapore. Electronic address: peterjb@bii.a-star.edu.sg.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Bond
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D006801:Humans; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D051193:Toll-Like Receptors
keywords: Innate immunity; Leucine-rich repeats; Pathogen associated molecular patterns; Signaling complex formation; Toll-like receptors; Transmembrane domain assembly