Description
FcγRI is the high affinity receptor for IgG, which is associated with autoimmune disease pathology and determines clinical responses to antibody-based immunotherapies. FcγRI has a complex evolutionary history that is not fully understood and to address this we explored signals of positive selection in the receptor’s functional gene, FCGR1A using codon-based selection tests of aligned orthologous placental mammalian sequences (n=32). Positive selection likely occurred, with two codons (H148 and W149) showing the strongest evidence of selection at adjacent positions known to form one of the two FcγRI-IgG binding interfaces. We employed ancestral reconstruction to statistically infer prior codon sequences at these sites and identified ancestral P148 and R149 codons at several different nodes in the phylogeny. Employing molecular dynamic simulations, we determined how evolutionary changes at these sites may have influenced the binding potential of FcγRI-IgG of modern-day Homo sapiens. A P148H change showed that protonation at physiological pH remained similar, yet during acidotic simulations we see protonation reduced by 49%, reducing affinity for IgG. R149W shows a potential role in electron conjugation and binding potential with zinc ions. Although there is an additional FcγRI-IgG interface, our data demonstrates that at this binding interface, these two codons have evolved to be less sensitive to shifts in pH and therefore promote a more stable interaction with the Fc portion of IgG.| Period | 8 Jan 2025 |
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| Event title | International Conference on Health, Medicine and Life Sciences (ICHMLS - 25) : Health, medicine and life sciences |
| Event type | Conference |
| Conference number | 6 |
| Location | Las Vegas, United States, NevadaShow on map |
| Degree of Recognition | International |
Keywords
- Bioinformatics
- biophysics
- Immunology