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Abstract
Toll-like receptor 2 (TLR2) initiates potent immune responses by recognizing diacylated
and triacylated lipopeptides. Its ligand specificity is controlled by whether it heterodimerizes
with TLR1 or TLR6. We have determined the crystal structures of TLR2-TLR6-diacylated
lipopeptide, TLR2-lipoteichoic acid, and TLR2-PE-DTPA complexes. PE-DTPA, 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N-diethylenetriaminepentaacetic
acid, is a synthetic phospholipid derivative. Two major factors contribute to the
ligand specificity of TLR2-TLR1 or TLR2-TLR6 heterodimers. First, the lipid channel
of TLR6 is blocked by two phenylalanines. Simultaneous mutation of these phenylalanines
made TLR2-TLR6 fully responsive not only to diacylated but also to triacylated lipopeptides.
Second, the hydrophobic dimerization interface of TLR2-TLR6 is increased by 80%, which
compensates for the lack of amide lipid interaction between the lipopeptide and TLR2-TLR6.
The structures of the TLR2-lipoteichoic acid and the TLR2-PE-DTPA complexes demonstrate
that a precise interaction pattern of the head group is essential for a robust immune
response by TLR2 heterodimers.
Copyright 2009 Elsevier Inc. All rights reserved.