Leucine-rich repeats and pathogen recognition in Toll-like receptors.
Toll-like receptors (TLRs) are the major cell-surface initiators of inflammatory responses to pathogens. They bind a wide variety of pathogenic substances through their ectodomains (ECDs). Here, we ask: what is the structural basis for this interaction? Toll-like receptor ECDs comprise 19-25 tandem copies of a motif known as the leucine-rich repeat (LRR). No X-ray structure of a TLR-ECD is currently available but there are several high-resolution LRR-containing proteins that can be used to model TLRs. We suggest that the basic framework of TLRs is a horseshoe-shaped solenoid that contains an extensive beta-sheet on its concave surface, and numerous ligand-binding insertions. Together, these insertions and the beta-sheet could provide a binding surface that is 10-fold greater in area than binding surfaces in antibodies and T-cell receptors.
Bell
Jessica K
JK
Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, Building 5, Room 338, National Institutes of Health, Bethesda, MD 20892, USA.
Mullen
Gregory E D
GE
Leifer
Cynthia A
CA
Mazzoni
Alessandra
A
Davies
David R
DR
Segal
David M
DM
D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D007111:Immunity, Cellular; D007930:Leucine; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000276:immunology; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000276:immunology; D020449:Repetitive Sequences, Amino Acid; D016415:Sequence Alignment; D051193:Toll-Like Receptors
D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D007930:Leucine