Toll-like receptor 1 (TLR1) is a member of thetoll-like receptor (TLR) family ofpattern recognition receptors (PRRs) that form the cornerstone of theinnate immune system.[5][6][7] TLR1 recognizes bacteriallipoproteins and glycolipids in complex withTLR2. TLR1 is acell surfacereceptor.[5] In humans, TLR1 is encoded by theTLR1gene, which is located onchromosome 4.[8]
The binding ofligands to TLR1 activates intracellularsignaling cascades leading to an inflammatory response and initiation of immune processes.[5][9]
TLR1 cooperates withTLR2 in the recognition of bacterial triacyl lipoproteins. TLR1 has been shown to recognize the outer surface lipoprotein ofBorrelia burgdorferi. The important role of TLR1 in recognizing triacyl lipopeptides has been shown in TLR1-deficient mice.[9][10]
Toll-like receptors, including TLR-1, found on the epithelial cell layer that lines the small and large intestine are important players in the management of thegut microbiota and detection of pathogens.[11]
TLR1 is synthesized in theendoplasmic reticulum. The trafficking of TLR1 fromendoplasmic reticulum is controlled byprotein associated with TLR4 (PRAT4A), which isendoplasmic reticulum residentchaperone. TLR1 is then transported toGolgi complex and tocell membrane.[12]
TLR1mRNA was expressed at high levels in the kidney, lung, and spleen in adult humans, but in low levels in fetal brain and liver as well as inHeLa cell line.[13]
TLR1 is expressed in the highest levels onNK cells compared to otherTLRs. TLR1 has been found to be expressed on human peripheral bloodγδT cells,myeloid-derived suppressor cells,platelets,CD4+ T cells,microglia,astrocytes, immaturedendritic cells, LTi-likeinnate lymphoid cells[12] andeosinophils.[14] It is also found on the surface ofmacrophages andneutrophils.[citation needed]
TLR1 is a type Itransmembraneglycoprotein composed of extracellular, transmembrane and intracellular domains.[5]
The extracellular domain of TLR1 containsleucine-rich repeat (LRR) domains, which play a crucial role in bindingPAMPs. TheLRR domains can be further categorized into three subdomains: the N-terminal, central, and C-terminal regions. While the N-terminal and C-terminal domains of TLR1 exhibit relative consistency with a consensusamino acid structure represented as xLxxLxxLxLxxNxLxxLPxxxFx, the central domains display significant variability. Notably, the central domains of TLR1 lack the presence of stabilizingasparagine ladders, which contribute to the typical horseshoe-like shape of the extracellular domain of TLRs. Furthermore, the number of residues within theLRR domains of the central region varies between 20 and 33 residues. Additionally, extraalpha helices were found in central domains of TLR1. The biological function of TLR1 is closely linked to the structural modifications in its extracellular domain, which are responsible for its capacity to bindligands.[15]
The intracellular domain of TLR1 consists of atoll/interleukin-1 receptor (TIR) domain, which is shared by various adaptor proteins involved in thesignaling cascade initiated byTLRs. TheTIR domain of TLR1 has been found as amonomer in the crystal structure.[16]
TLR1 is able to recognizeligands as a complex withTLR2, referred to as TLR2/1heterodimer.TLR2 can heterodimerize also withTLR6 forming TLR2/6 heterodimer. TLR2/1 adopts an "m"-shaped conformation when interacted with itsligands. The "m" shape conformation is formed by extracellular domains of TLR1 andTLR2, bringing the transmembrane and intracellular domains in close association. This conformational arrangement subsequently triggers a downstreamsignaling cascade.[16][17]
TLR2/1 specifically recognizes triacyllipopeptides, whereas TLR2/6 recognizes diacyllipopeptides. Diacyl and triacyllipopeptides are present on the bacterial outer membrane. In the case of triacyl lipopeptides, the mechanism behind their recognition lies in the incorporation of two lipid chains into the hydrophobic pocket ofTLR2, while the remaining lipid chain inserts into a hydrophobic pocket of TLR1. RegardingTLR6, the hydrophobic pocket is obstructed by the side chains of twophenylalanine residues, resulting in a smaller pocket than in TLR1. This structural difference accounts for the distinct ligand specificities exhibited by TLR2/1 and TLR2/6 heterodimers.[17]
TLR1 has been shown tointeract withTLR2.[18] TLR1 recognizespeptidoglycan and (triacyl)lipopeptides in concert withTLR2 (as a heterodimer).[19][20]
This article incorporates text from this source, which is available under theCC BY 4.0 license.This article incorporates text from theUnited States National Library of Medicine ([1]), which is in thepublic domain.
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