Identification of a unique TLR2-interacting peptide motif in a microbial leucine-rich repeat protein.
Pathogenesis of many bacterially-induced inflammatory diseases is driven by Toll-like receptor (TLR) mediated immune responses following recognition of bacterial factors by different TLRs. Periodontitis is a chronic inflammation of the tooth supporting apparatus often leading to tooth loss, and is caused by a Gram-negative bacterial consortium that includes Tannerella forsythia. This bacterium expresses a virulence factor, the BspA, which drives periodontal inflammation by activating TLR2. The N-terminal portion of the BspA protein comprises a leucine-rich repeat (LRR) domain previously shown to be involved in the binding and activation of TLR2. The objective of the current study was to identify specific epitopes in the LRR domain of BspA that interact with TLR2. Our results demonstrate that a sequence motif GC(S/T)GLXSIT is involved in mediating the interaction of BspA with TLR2. Thus, our study has identified a peptide motif that mediates the binding of a bacterial protein to TLR2 and highlights the promiscuous nature of TLR2 with respect to ligand binding. This work could provide a structural basis for designing peptidomimetics to modulate the activity of TLR2 in order to block bacterially-induced inflammation.
Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, NY 14214, USA.
Srinivas R
SR
Myneni
Rajendra P
RP
Settem
Hakimuddin T
HT
Sojar
James P
JP
Malone
Vuokko
V
Loimaranta
Takuma
T
Nakajima
Ashu
A
Sharma
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D041963:Bacteroidetes / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007930:Leucine; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D010518:Periodontitis / Q000382:microbiology; D060066:Protein Interaction Maps; D017434:Protein Structure, Tertiary; D051195:Toll-Like Receptor 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014357:Trypsin / Q000737:chemistry
D001426:Bacterial Proteins; C105995:BspA protein, bacteria; D008565:Membrane Proteins; D010446:Peptide Fragments; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D014357:Trypsin; D007930:Leucine