The Polymorphism P315L of Human Toll-Like Receptor 1 Impairs Innate Immune Sensing of Microbial Cell Wall Components

Omueti, Katherine O.; Mazur, Daniel J.; Thompson, Katherine S.; Lyle, Elizabeth A.; Tapping, Richard I.

doi:10.4049/jimmunol.178.10.6387

Cited by 79 publications

(60 citation statements)

References 40 publications

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“…Most interestingly, the aminoacid substitution resulting from the derived allele of rs3923647 results in a modest loss of TLR1 activity as measured by luciferase assay. 30 Of these, only rs5743511 was at a high enough frequency to test for selection but could not produce a separate signal from rs5743618 or rs4833095.…”

Section: Positive Selection and Distribution Of Rs5743612mentioning

confidence: 99%

“…29,30 In addition, it has been linked to disease risk in populations where the derived allele of rs5743618 is 45% frequency, such as IgA nephropathy in Koreans 50 and placental malaria in Ghanians. 31 This, at the very least, suggests a phenotypic effect on a variant linked to rs4833095 independent of rs5746318, if not rs4833095 itself.…”

Section: Distribution and Positive Selection On Missense Variants At mentioning

confidence: 99%

“…In addition, previous studies involving TLR1 constructs with both states of the amino-acid substitution, serine and asparagine, have produced mixed results regarding functionality. 29,30 We tested the derived allele at rs4833095 for positive selection using REHH in all global populations. In India and East Asia, and to a lesser degree in the Pacific Islands and the Middle East, it achieved significance by REHH but not with iHS.…”

Section: Distribution and Positive Selection On Missense Variants At mentioning

confidence: 99%

“…28 There exists, however, considerable genetic diversity in TLR1 beyond rs5743618, including multiple, high-frequency (45% in at least one population) missense variants. Multiple SNPs, such as rs4833095, rs3923647, and rs5743613, have direct evidence suggesting an effect on TLR1 activity, 30 whereas others have been linked through association studies. 22,27,31,32 There is evidence that some of these alleles may be under selective pressure.…”

Section: Introductionmentioning

confidence: 99%

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Haplotype structure and positive selection at TLR1

et al. 2013

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Toll-like receptor 1, when dimerized with Toll-like receptor 2, is a cell surface receptor that, upon recognition of bacterial lipoproteins, activates the innate immune system. Variants in TLR1 associate with the risk of a variety of medical conditions and diseases, including sepsis, leprosy, tuberculosis, and others. The foremost of these is rs5743618 c.2079T4G(p. (Ile602Ser)), the derived allele of which is associated with reduced risk of sepsis, leprosy, and other diseases. Interestingly, 602Ser, which shows signatures of selection, inhibits TLR1 surface trafficking and subsequent activation of NFjB upon recognition of a ligand. This suggests that reduced TLR1 activity may be beneficial for human health. To better understand TLR1 variation and its link to human health, we have typed all 7 high-frequency missense variants (45% in at least one population) along with 17 other variants in and around TLR1 in 2548 individuals from 56 populations from around the globe. We have also found additional signatures of selection on missense variants not associated with rs5743618, suggesting that there may be multiple functional alleles under positive selection in this gene.

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Section: Positive Selection and Distribution Of Rs5743612mentioning

confidence: 99%

Section: Distribution and Positive Selection On Missense Variants At mentioning

confidence: 99%

Section: Distribution and Positive Selection On Missense Variants At mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Haplotype structure and positive selection at TLR1

et al. 2013

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“…The hydrophobic "patch" is composed of P315', Y320', V311', V339' and L359' on TLR1 (where an apostrophe corresponds to TLR1) and Y323, L324, F322, P352, Y376, L350, F349, L371 and V373 on TLR2 [10]. Polymorphic variants of TLR1 without P315' present in the interfacial hydrophobic core exhibit inhibited signaling behavior [36]. The hydrophilic region bordering the hydrophobic patch forms hydrogen bonds including K385'-N345, T361'/T363'-K347, R337'-E375, and Q383'-H398, and ionic interactions are formed via E321'-H318/R321, E366'-R321, K385'-E369, R337'-E374, and D310'-K378 [10].…”

Section: Tlr1-tlr2 and Tlr2-tlr6 Heterodimersmentioning

confidence: 99%

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

Berglund

Kargas

Ortiz-Suarez

et al. 2015

Progress in Biophysics and Molecular Biology

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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.

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Genomic variants of TLR1 – It takes (TLR‐)two to tango

Schumann

Tapping

2007

Eur J Immunol

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Toll-like receptors (TLR) are innate immune sensors of microbial cell wall products that initiate early host responses. The TLR2 receptor complex has been shown to contain heterodimers of TLR2 with either TLR1 or TLR6 enabling the host to detect different microbial molecules, such as lipopeptides of different chemical composition. In this issue of the European Journal of Immunology, an important role in the sensing of microbial products for I602S, a single nucleotide polymorphism (SNP) in human TLR1 has been identified. This result, in combination with another recently published report on this polymorphism elucidating a functional role in cell trafficking (surface expression of the receptor complex in individuals carrying the SNP was altered), provide genetic evidence affirming the important function of TLR1 as an essential coreceptor for TLR2. Sensing of microbial products and the immediate inflammatory response are critical for an effective host defense. Toll-like receptors (TLR) have emerged over the past ten years as essential pattern recognition receptors of the innate immune system that act by sensing foreign molecules of viral, microbial, fungal, protozoal and helminth origin. Activation of TLR induces the expression of gene products involved in direct killing of the pathogen, inflammatory processes, and the initiation of events required for adaptive immune responses. Of the ten human TLR, several are expressed within intracellular endosomes where they mediate recognition of viral and bacterial nucleic acids (TLR3, and TLR7-TLR9). All others are expressed on the cell surface including TLR4, the sensor of Gram-negative lipopolysaccharide (LPS), and TLR5, which senses bacterial flagellin. A variety of microbial and fungal components are sensed by TLR2, and it has been shown that TLR1 and TLR6 are coreceptors for TLR2 forming either TLR2/1 or TLR2/6 heterodimers with differing agonist specificities [1]. TLR1 and TLR2 cooperate to sense triacylated bacterial lipoproteins, while TLR6 and TLR2 recognize certain diacylated lipoproteins, although this theory was recently challenged and modified [2]. It has been hypothesized that by forming heterodimers, a wider variety of microbial products are sensed by the TLR2 complex and this ability is extended by additional coreceptors such as CD14 and CD36, as well as by soluble serum factors such as lipopolysaccharide binding protein (LBP) [3,4]. Eur. J. Immunol. 2007. 37: 2059-2062 In a recent study conducted by us [7], we also identified I602S as a functionally relevant SNP. This finding arose from the observation that blood-derived monocytes from certain individuals appeared to completely lack cell surface TLR1 expression. The frequency of the observation, as well as the position of I602S within the receptor, led us to investigate the role of I602S in this phenotype. Similar to Hawn et al., [6], we found that blood cells derived from individuals homozygous for 602S exhibited attenuated responses to triacylated lipopeptides [7]. We were also able to reconstitute the ph...

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The Polymorphism P315L of Human Toll-Like Receptor 1 Impairs Innate Immune Sensing of Microbial Cell Wall Components

Cited by 79 publications

References 40 publications

Haplotype structure and positive selection at TLR1

Haplotype structure and positive selection at TLR1

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

Genomic variants of TLR1 – It takes (TLR‐)two to tango

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