Structural analyses of human Toll-like receptor 4 polymorphisms D299G and T399I.
BACKGROUND
TLR4 polymorphism replacing Asp-299 with Gly and Thr-399 with Ile (D299G/T399I) causes LPS hyporesponsiveness.


RESULTS
TLR4(SNPs)·MD-2·LPS exhibits an agonistic 2:2:2 architecture. Local structural differences were observed around D299G, but not around T399I, SNP site.


CONCLUSIONS
These local differences cause the modulation of surface properties of TLR4, which may affect ligand binding.


CONCLUSIONS
This study provides structural evidence of the functionality of the mutant TLR4 carrying the SNPs. Toll-like receptor 4 (TLR4) and its coreceptor MD-2 recognize bacterial lipopolysaccharide (LPS) and signal the innate immune response. Two single nucleotide polymorphisms (SNPs) of human TLR4, D299G and T399I, have been identified and suggested to be associated with LPS hyporesponsiveness. Moreover, the SNPs have been proposed to be associated with a variety of infectious and noninfectious diseases. However, how the SNPs affect the function of TLR4 remains largely unknown. Here, we report the crystal structure of the human TLR4 (D299G/T399I)·MD-2·LPS complex at 2.4 Å resolution. The ternary complex exhibited an agonistic "m"-shaped 2:2:2 architecture that was similar to that of the human wild type TLR4·MD-2·LPS complex. Local structural differences that might affect the binding of the ligands were observed around D299G, but not around T399I, SNP site.
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Tokyo 113-0033, Japan.
Umeharu
U
Ohto
Natsuko
N
Yamakawa
Sachiko
S
Akashi-Takamura
Kensuke
K
Miyake
Toshiyuki
T
Shimizu
D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D006801:Humans; D008070:Lipopolysaccharides / Q000737:chemistry / Q000378:metabolism; D051218:Lymphocyte Antigen 96 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D051197:Toll-Like Receptor 4 / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
C495377:LY96 protein, human; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4