The pathogenic effect of SNPs on structure and function of human TLR4 using a computational approach

Area of Science:

• Immunology
• Genetics
• Structural Biology

Background:

• Single nucleotide polymorphisms (SNPs) in human toll-like receptor 4 (hTLR4) are linked to various diseases, including cancer and immune disorders.
• The structural and functional consequences of hTLR4 SNPs remain incompletely understood.

Purpose of the Study:

• To investigate the biological and structural impacts of hTLR4 SNPs.
• To identify specific hTLR4 SNPs that cause structural damage and functional impairment.

Main Methods:

• Screening of 7910 hTLR4 SNPs to identify damaging variants.
• Structural analysis of identified SNPs, focusing on mutations in the extracellular region and their effect on protein conformation.
• Prediction of changes in interactions with key molecules like myeloid differentiation factor 2 (MD-2) and lipopolysaccharide (LPS).

Main Results:

• Identified 21 damage-causing hTLR4 SNPs, with three deleterious and one moderate mutation in the extracellular region.
• These mutations cause significant conformational changes in the Leucine-rich repeat (LRR) arc, altering its dimensions.
• Mutant hTLR4 structures show impaired binding to HMGB1 and LPS, and reduced MD-2 interaction, affecting normal signaling.

Conclusions:

• Specific hTLR4 SNPs induce structural alterations that disrupt receptor function.
• These functional impairments contribute to the pathogenesis of sepsis, cancer, genetic disorders, and other immune-related diseases.
• The findings highlight the critical role of hTLR4 structure in immune response and disease susceptibility.