A network of hydrogen bonds on the surface of TLR2 controls ligand positioning and cell signaling.
TLR2 is a pattern recognition receptor that functions in association with TLR1 or TLR6 to mediate innate immune responses to a variety of conserved microbial products. In the present study, the ectodomain of TLR2 was extensively mutated, and the mutants were assessed for their ability to bind and to mediate cellular responses to triacylated lipopeptide Pam(3)CSK(4). This analysis provides evidence that the recently published crystal structure of the TLR2-TLR1-Pam(3)CSK(4) complex represents a functional signal-inducing complex. Furthermore, we report that extended H-bond networks on the surface of TLR2 are critical for signaling in response to Pam(3)CSK(4) and to other di- and tri-acylated TLR2-TLR6 and TLR2-TLR1 ligands. Based on this finding, we suggest a dynamic model for TLR2-mediated recognition of these ligands in which TLR2 fluctuates between a conformation that is more suitable for binding of the fatty acyl moieties of the ligands and a conformation that favors, via a specific orientation of the ligand head group, formation of a signal-inducing ternary complex.
Kajava
Andrey V
AV
Centre de Recherches de Biochimie Macromoléculaire, Montpellier Cedex 5, France.
Vasselon
Thierry
T
D019760:Amidine-Lyases / Q000378:metabolism; D000081247:CSK Tyrosine-Protein Kinase; D002460:Cell Line; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D006899:Mixed Function Oxygenases / Q000378:metabolism; D046912:Multiprotein Complexes / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000737:chemistry / Q000378:metabolism*; D019061:src-Family Kinases
D008024:Ligands; D046912:Multiprotein Complexes; D011518:Proto-Oncogene Proteins; D051195:Toll-Like Receptor 2; D006899:Mixed Function Oxygenases; C544787:PAM protein, human; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D019760:Amidine-Lyases