Protein Name

Toll-like receptor1 (TLR1)/TLR2/lipopeptide complex


Homo sapiens (human)

Biological Context

The immune system is the most important biological defense system for organisms. It can be divided into two systems: innate immune system and adaptive immune system. In the adaptive immune system, an antibody can specifically recognize its antigen. In the innate immune system, on the other hand, pattern recognition receptors (PPRs) recognize pathogen-associated molecular patterns (PAMPs), which commonly exist in pathogenic microorganisms.

Toll-like receptors (TLRs) are membrane proteins belonging to the innate immune system as members of PPRs. TLRs recognize pathogen-specific components and start the signal cascade for the immune response. At present, more than 10 TLRs of mammal are known, which recognize pathogen specific components, such as lipoproteins, lipopolysaccharide and flagellin. TLRs recognize PAMPs at their extracellular region, activating an adaptor protein which is bound to the intracellular region of TLR, and the signal cascade starts.

TLR1, TLR2 and TLR6 recognize lipoproteins or lipopeptides from Mycoplasma, and their active forms are heterodimers. The TLR1-TLR2 complex can bind to tri-acylated lipopeptides (Fig. 1), The TLR2-TLR6 complex can bind to di-acylated lipopeptides (Fig. 2).

(Fig. 1) Tri-acylated lipopeptide (Pam3CSK4).
(Fig. 2) Di-acylated lipopeptide (Pam2CSK4).

Structure Description


TLR is a membrane protein with one transmembrane segment. It recognizes a ligand at the extracellular domain, and the intracellular domain, named TIR domain, starts the signal cascade. This crystal structure is a complex of extracellular domains of TLR1 and TLR2 with a tri-acylated lipopeptides, Pam3CSK4 (Fig. 3, 4). TLR1 and TLR2 form typical leucine rich repeat structures and have 3 domains: N terminal, central and C terminal domains. Both ligand binding and dimerization of TLR1 and TLR2 occur in the central domain. A tri-acylated lipopeptides, Pam3CSK4, induced the "m" shaped TLR1-TLR2 heterodimerization (Fig. 3). In contrast, Pam2CSK4 does not work with for TLR1 and TLR2. This result is consistent with the fact that TLR1 is crucial for the recognition of tri-acylated lipopeptides. The two ester-bound lipid chains of Pam3CSK4 are inserted into a pocket in TLR2, while the amide-bound lipid chain is inserted into a hydrophobic channel in TLR1 (Fig. 4).

An activation model is proposed where dimerization of the extracellular domains of TLRs also induces the dimerization of intracellular TIR domains and therefore initiate signaling (Fig. 5). Thus the determination of full length structure of the TLR1-TLR2 complex is expected.

2Z7X_side_view (Fig. 3) TLR1-TLR2-Pam3CSK4 complex.
TLR1 (yellow), TLR2 (aqua) and Pam3CSK4 (red).
This is a complex structure of extracellular domains of TLRs.
Cell membrane is just below the complex (see Fig. 5).
2Z7X_top_view (Fig. 4) TLR1-TLR2-Pam3CSK4 complex.
The top view of the complex. the colors are same as Fig. 3.
model (Fig. 5) A model of lipopeptide-induced dimerization.
Heterodimerization model of TLR1 and TLR2 induced by the ligand binding.
The dimerization of extracellular domains enables intracellular domains closer. Subsequently it may induce dimerization of intracellular domain and initiate signaling.

Protein Data Bank (PDB)



Jin, M.S. Kim, S.E. Heo, J.Y. Lee, M.E. Kim, H.M. Paik, S.G. Lee, H. Lee, J.O.; "Crystal Structure of the TLR1-TLR2 Heterodimer Induced by Binding of a Tri-Acylated Lipopeptide"; Cell(Cambridge,Mass.); (2007) 130:1071-1082 PubMed:17889651.


  • UniProt:Q15399 Toll-like receptor1 (TLR1)
  • UniProt:O60603 Toll-like receptor2 (TLR2)
  • UniProt:Q4G1L2 Variable lymphocyte receptor B (a part of this protein sequence was added to the end of TLR1 and TLR2 to facilitate the production and crystallization)

author: Naoya Fujita

Japanese version:PDB:2Z7X