Crystal Structure of the TLR1-TLR2 Heterodimer Induced by Binding of a Tri-Acylated Lipopeptide

Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejon, Korea 305-701.
Cell (Impact Factor: 32.24). 10/2007; 130(6):1071-82. DOI: 10.1016/j.cell.2007.09.008
Source: PubMed


TLR2 in association with TLR1 or TLR6 plays an important role in the innate immune response by recognizing microbial lipoproteins and lipopeptides. Here we present the crystal structures of the human TLR1-TLR2-lipopeptide complex and of the mouse TLR2-lipopeptide complex. Binding of the tri-acylated lipopeptide, Pam(3)CSK(4), induced the formation of an "m" shaped heterodimer of the TLR1 and TLR2 ectodomains whereas binding of the di-acylated lipopeptide, Pam(2)CSK(4), did not. The three lipid chains of Pam(3)CSK(4) mediate the heterodimerization of the receptor; the two ester-bound lipid chains are inserted into a pocket in TLR2, while the amide-bound lipid chain is inserted into a hydrophobic channel in TLR1. An extensive hydrogen-bonding network, as well as hydrophobic interactions, between TLR1 and TLR2 further stabilize the heterodimer. We propose that formation of the TLR1-TLR2 heterodimer brings the intracellular TIR domains close to each other to promote dimerization and initiate signaling.

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    • "The mammalian TLR2 has to heterodimerize with TLR1 or TLR6 in order to bind tri-or di-acetlyated lipopetides, respectively (Jin et al., 2007). Piscine Tlr2 might possibly undergo functional pairing with Tlr1, but a TLR6 ortholog is absent in teleosts (Palti, 2011; Rebl et al., 2010; Zhang et al., 2014). "
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    ABSTRACT: The mammalian Toll-like receptor 2 (TLR2) is a dominant receptor for the recognition of Gram-positive bacteria. Its structure and functional properties were unknown in salmonid fish. In RT-PCR and RACE experiments, we obtained the full-length cDNA sequence encoding Tlr2 from rainbow trout (Oncorhynchus mykiss) as well as a copy of an unspliced nonsense message from a highly segmented gene. The primary structure of the encoded receptor complies with the domain structure and ligand-binding sites known from mammals and other fish species and sorts well into the evolutionary tree of teleostean Tlr2s. We retrieved a gene version encoding the receptor on a single exon (tlr2a) and also a partial sequence of a second gene variant being segmented into multiple exons (tlr2b). Surprisingly, the abundances of both transcript variants accounted only for ∼10% of all Tlr2-encoding transcripts in various tissues and cell types of healthy fish. This suggests the expression of several distinct tlr2 gene variants in rainbow trout. We expressed tlr2a in HEK-293 cells, but were unable to demonstrate its functionality through NF-κB activation. Neither synthetic lipopeptides known to stimulate mammalian TLR2 nor different bacterial challenges induced OmTLR2-mediated NF-κB activation, not in HEK-293 or in salmon CHSE-214 cells. Positive demonstration of TLR2-MYD88 interaction excluded that its functional impairment caused the failure of NF-κB activation. We discuss impaired heterodimerization with a necessary Tlr partner as one from among several alternatives to explain the dysfunction of Tlr2a in the interspecies reconstitution system of TLR signaling.
    Developmental and comparative immunology 09/2015; DOI:10.1016/j.dci.2015.08.012 · 2.82 Impact Factor
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    • "We sequenced a 1149-bp fragment of TLR2 for all individuals (N = 385) (Table 1) in acordance with previously reported protocols (Tschirren et al., 2012). The amplified fragment contains the functionally relevant sites involved in pathogen recognition and TLR heterodimerization (Jin et al., 2007) (see Supporting information, Fig. S1), and we previously demonstrated molecular signatures of positive selection during the evolutionary history of rodents within this gene region (Tschirren, R aberg & Westerdahl , 2011). TLR2 amplifications were performed in a total volume of 10 lL containing 0.2 lL of "
    Dataset: Morger 2015

    • "The first involves direct TLR–ligand interaction such as TLR3–dsRNA interaction (Liu et al., 2008). The second involves TLR homo-or heterodimerization, for example TLR1–TLR2 interact through a hydrophobic lipopeptide that fits in an internal hydrophobic pocket of the other (Jin et al., 2007). The third involves the use of co-receptors and accessory molecules, for instance the structure of the TLR4–MD2–LPS complex (Park et al., 2009; Piccinini and Midwood, 2010). "
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    ABSTRACT: Accumulating evidence indicates that aging is associated with a chronic low-level inflammation, termed sterile-inflammation. Sterile-inflammation is a form of pathogen-free inflammation caused by mechanical trauma, ischemia, stress or environmental conditions such as ultra-violet radiation. These damage-related stimuli induce the secretion of molecular agents collectively termed danger-associated molecular patterns (DAMPs). DAMPs are recognized by virtue of specialized innate immune receptors, such as toll-like receptors (TLRs) and NOD-like receptor family, pyrin domain containing 3 (NLRP3). These receptors initiate signal transduction pathways, which typically drive inflammation in response to microbe-associated molecular patterns (MAMPs) and/or DAMPs. This review summarizes the current knowledge on DAMPs-mediated sterile-inflammation, its associated downstream signaling, and discusses the possibility that DAMPs activating TLRs or NLRP3 complex mediate sterile inflammation during aging and in aging-related pathologies. Copyright © 2015. Published by Elsevier B.V.
    Ageing Research Reviews 01/2015; 24(Pt A). DOI:10.1016/j.arr.2015.01.003 · 4.94 Impact Factor
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