Molecular insights into the interaction between human nicotinamide phosphoribosyltransferase and Toll-like receptor 4
Journal of Biological Chemistry, ISSN: 0021-9258, Vol: 298, Issue: 3, Page: 101669
2022
- 13Citations
- 16Captures
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Example: if you select the 1-year option for an article published in 2019 and a metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019. If you select the 3-year option for the same article published in 2019 and the metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019, 2018 and 2017.
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Metrics Details
- Citations13
- Citation Indexes13
- 13
- Captures16
- Readers16
- 16
Article Description
The secreted form of the enzyme nicotinamide phosphoribosyltransferase (NAMPT), which catalyzes a key reaction in intracellular NAD biosynthesis, acts as a damage-associated molecular pattern triggering Toll-like receptor 4 (TLR4)-mediated inflammatory responses. However, the precise mechanism of interaction is unclear. Using an integrated approach combining bioinformatics and functional and structural analyses, we investigated the interaction between NAMPT and TLR4 at the molecular level. Starting from previous evidence that the bacterial ortholog of NAMPT cannot elicit the inflammatory response, despite a high degree of structural conservation, two positively charged areas unique to the human enzyme (the α1-α2 and β1-β2 loops) were identified as likely candidates for TLR4 binding. However, alanine substitution of the positively charged residues within these loops did not affect either the oligomeric state or the catalytic efficiency of the enzyme. The kinetics of the binding of wildtype and mutated NAMPT to biosensor-tethered TLR4 was analyzed. We found that mutations in the α1-α2 loop strongly decreased the association rate, increasing the K D value from 18 nM, as determined for the wildtype, to 1.3 μM. In addition, mutations in the β1-β2 loop or its deletion increased the dissociation rate, yielding K D values of 0.63 and 0.22 μM, respectively. Mutations also impaired the ability of NAMPT to trigger the NF-κB inflammatory signaling pathway in human cultured macrophages. Finally, the involvement of the two loops in receptor binding was supported by NAMPT-TLR4 docking simulations. This study paves the way for future development of compounds that selectively target eNAMPT/TLR4 signaling in inflammatory disorders.
Bibliographic Details
http://www.sciencedirect.com/science/article/pii/S0021925822001090; http://dx.doi.org/10.1016/j.jbc.2022.101669; http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85125739625&origin=inward; http://www.ncbi.nlm.nih.gov/pubmed/35120922; https://linkinghub.elsevier.com/retrieve/pii/S0021925822001090; https://dx.doi.org/10.1016/j.jbc.2022.101669
Elsevier BV
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