Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide.
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.
Jin
Mi Sun
MS
Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejon, Korea 305-701.
Kim
Sung Eun
SE
Heo
Jin Young
JY
Lee
Mi Eun
ME
Kim
Ho Min
HM
Paik
Sang-Gi
SG
Lee
Hayyoung
H
Lee
Jie-Oh
JO
D000215:Acylation; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D003001:Cloning, Molecular; D003461:Crystallography; D019281:Dimerization; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007113:Immunity, Innate; D055666:Lipopeptides; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D015398:Signal Transduction; D051194:Toll-Like Receptor 1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051216:Toll-Like Receptor 6 / Q000737:chemistry
D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; D010455:Peptides; C495342:TLR2 protein, human; C493486:Tlr2 protein, mouse; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6