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bioRxiv · 10.1101/2024.07.30.605793

Sequence and structural analysis of adaptors of Toll-like receptor 4 sheds light on the evolutionary trajectory and functional emergence

Verma, S.·Sowdhamini, R.
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Abstract

1.Type 4 Toll-like receptors 4 (TLR4) recognise lipopolysaccharides (LPS) from bacteria as their conventional ligands and undergo downstream signalling to produce cytokines. They mediate the signalling either by the TIRAP-MyD88 complex or by the TRAM-TRIF complex. The MyD88 pathway is common to all other TLRs, whereas the TRAM-TRIF complex is largely exclusive to TLR4. We studied the TIR domain of TRAM and TRIF homologue proteins, that are crucial for downstream signalling. From our previous work on pan-genome-wide survey, we find Callorhincus milli to be the ancestral organism with both TRAM and TRIF proteins. To gain a deeper insight about the functioning of these proteins and comparison with the adaptor proteins in Homo sapiens, we performed TRAM and TRIF dimer docking to model the TRAM-TRIF complex of representative organisms across various taxa. These provide us insights to ascertain a possible interaction surface, calculate the energetics, electrostatic potential, and then employ Normal Mode Analysis (NMA) to examine fluctuating, interacting and specific residue clusters which can be important for the protein functioning in both organisms. We also performed molecular dynamics simulations of these complexes and cross validated the functionally important residues using network parameters. While the critical residues of TIRAP, TRIF, and MyD88 were preserved, we found that the important residues of TRAM signalling were not conserved in Callorhincus milli. This suggests the presence of functional TIRAP-MyD88 mediated TLR4 signalling and TRIF mediated TLR3 signalling in the ancestral species. The overall biological function of this signalling domain appears to be gradually acquired through the orchestration of several motifs through evolutionary scale.

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Verma, S., Sowdhamini, R.. 2024-07-30. Sequence and structural analysis of adaptors of Toll-like receptor 4 sheds light on the evolutionary trajectory and functional emergence. https://doi.org/10.1101/2024.07.30.605793

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