TLR1

TLR1 Full Name

toll-like receptor 1

TLR1 Introduction

TLR1 is a pattern recognition receptor and a member of the TLR family. PRRs are a class of receptors of the innate immune system. TLR1 is necessary for the innate immune response to foreign pathogens. TLR1 has the typical architecture of other members of the TLR family. It is composed of three major domains, an extracellular LRR domain that senses PAMPs, a transmembrane domain and an intracellular TIR domain that activates downstream signaling cascades. TLR1 does not act as a receptor independently, instead it heterodimerizes with a second member of the TLR family, TLR2 to form a functional receptor complex that will bind its ligands.

Figure 1. Overview of Toll-like receptor signaling pathways. (Source: Chen YH, et al. 2024)

The TLR1/TLR2 heterodimer preferentially recognizes triacylated lipopeptides of Gram-positive bacteria and mycobacterial cell walls. This interaction is structure-specific. Crystal structures revealed that when binding to a triacylated lipopeptide, two of its lipid chains insert into a hydrophobic pocket on TLR2, while the third lipid chain is specifically accommodated by a hydrophobic channel in TLR1. This unique TLR1 channel is what enables the TLR1/TLR2 complex to recognize triacylated lipopeptides (as opposed to the TLR2/TLR6 complex that specializes in recognition of diacylated lipopeptides). After successful ligand recognition the intracellular TIR domains of TLR1 and TLR2 dimerize and serve as a platform for signaling which allows for the recruitment of the essential adaptor protein MyD88. This triggers a classical MyD88-dependent signaling pathway and subsequent activation of the NF-κB and MAPK pathways that results in the transcription and expression of many pro-inflammatory cytokines and chemokines that serve to mediate initiation and modulation of the innate immune response.

The malfunction or genetic polymorphism of TLR1 is closely associated with human disease predisposition and phenotypes. One of the best described linkages is to leprosy. Several independent studies have consistently shown that a common SNP in TLR1 is strongly associated with leprosy susceptibility. Carriers of the 602S allele show increased resistance to leprosy, suggesting a protective role. Molecular studies have shown that I602S polymorphism results in reduced intracellular trafficking of TLR1 and decreased TLR1 surface expression, culminating in defective cellular response to bacterial lipopeptides. However, this "loss-of-function" phenotype is potentially beneficial to the host, as it dampens the harmful inflammation caused by M. leprae, and prevents immunopathological damage. TLR family members have also been implicated in the development of chronic inflammatory conditions, such as atherosclerosis and IBD.

Alternate Names for TLR1

TLR1; toll-like receptor 1; TIL; CD281; rsc786; TIL. LPRS5; toll/interleukin-1 receptor-like protein

• 1. Noreen M, et al. Association of TLR1, TLR2, TLR4, TLR6, and TIRAP polymorphisms with disease susceptibility. Immunol Res. 2015 Jun;62(2):234-52.
  2. Chen YH, et al. Unraveling the Complexities of Toll-like Receptors: From Molecular Mechanisms to Clinical Applications. Int J Mol Sci. 2024 May 5;25(9):5037.