Abstract
The proteins S100A9 and S100A12 are associated with the human S100 calcium-binding protein family. These proteins promote interaction with target proteins and alter their conformation when they bind to calcium ions in EF-hand motifs. The V domain of RAGE (Receptor for Advanced Glycation End products) is crucial for S100A9 binding. The binding of RAGE with S100 family proteins aids in cell proliferation. In this report, we demonstrate that S100A12 protein hinders the binding of S100A9 with the RAGE V-domain. We used fluorescence and NMR spectroscopy to analyze the interaction of S100A9 with S100A12. The binary complex models of S100A9-S100A12 were developed using data obtained from 1H-15N HSQC NMR titrations and the HADDOCK program. We overlaid the complex models of S100A9-S100A12 with the same orientation of S100A9 and the RAGE V-domain. This complex showed that S100A12 protein blocks the interaction between S100A9 and the RAGE V-domain. It means S100A12 may be used as an antagonist for S100A9. The results could be favorable for developing anti-cancer drugs based on S100 family proteins.
Highlights
The interaction mechanisms of S100 family proteins could be useful for inhibiting their interaction in humans with the V-domain of RAGE (Receptor for Advanced Glycation End products)
The interface region was identified based on changes in residue signals
After exam the S100A9 HSQC spectra with and without the unlabeled S100A12, the results show that residues of S100A9 protein were involved in the interaction with S100A12 protein based on perturbation and cross-peaks decreasing in the HSQC spectra of S100A9 (Fig 1A)
Summary
The interaction mechanisms of S100 family proteins could be useful for inhibiting their interaction in humans with the V-domain of RAGE (Receptor for Advanced Glycation End products). The S100 protein family is the largest group of calcium-binding proteins. S100A9 and S100A12 are phagocyte-specific S100 family members that include the group of calgranulins. These proteins expression patterns are a major source of myeloid origin cells, which could be advantageous for identifying these proteins [5]. These proteins are called calprotectin proteins, which mostly occur in high concentrations within sites of inflammation associated with cancers [6], cystic fibrosis [7], rheumatoid arthritis [8], and other diseases [9]
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