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

ABSTRACT

The human toll-like receptor (hTLR) 4 single nucleotide polymorphisms (SNPs) are interconnected with cancer, multiple genetic disorders and other immune-related diseases. The detrimental effect of SNPs in hTLR4 with respect to structure and function has not been explored in depth. The present study concatenates the biological consequences of the SNPs along with structural modifications predicted at the hTLR4 gene. A total of 7910 SNPs of hTLR4 were screened, and 21 damage-causing SNPs were identified. Out of 21, seven are present in the extracellular region, of which three were detected as deleterious and the fourth one as moderate. These three mutations are located in a highly conserved region and influence conformational change. The change leads to the widening of the Leucine-rich repeat (LRR) arc to a maximum of 16.9 Å and a minimum of 8.7 Å. Expansion/shortening of LRR arc, never discussed before, would cause loss of myeloid differentiation factor 2 (MD-2) interactions in the interior and diminish lipopolysaccharide (LPS) responses. Similarly, in all mutant structures, the binding region for HMGB1 and LPS is deflating or in an unsupportive conformation. Thus, SNPs affect the regular signaling cascade and might result in human sepsis, genetic disorders, cancer and other immunological related diseases.Communicated by Ramaswamy H. Sarma.