Interaction of the S100A6 mutant (C3S) with the V domain of the receptor for advanced glycation end products (RAGE)

Mohan, Sumathy; Gupta, Arun; Yu, Chin

doi:10.1016/j.bbrc.2013.03.049

Cited by 32 publications

(48 citation statements)

References 32 publications

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“…The residues that exhibited a large decrease in cross-peak intensities were mapped onto the RAGE V domain structure to define the S100P binding site and distributed over discontinuous regions comprising of L4, L6 and L8 loops and the β3 and β6 strands, as shown in Figure 4c . Previous studies have described the importance of the interfacial residues R48, K52, R104 and K110 in the interaction of the RAGE V domain with its known binding partners, including S100B, S100A6 and AGE [22], [44], [74], [75]. The role of these solvent accessible residues has been further substantiated in this analysis of the S100P-RAGE V domain complex.…”

Section: Resultssupporting

confidence: 60%

“…For S100A11, the V domain-binding residues are located in helix-2 and helix-4 [89]. The model of the S100A6-RAGE V domain complex suggests that the RAGE V domain-binding surface of S100A6 is predominantly distributed over loop 1, loop 3 and helix 4 [75]. These differences in the binding interfaces between various S100 proteins and RAGE suggest that RAGE recognizes its S100 ligands based on their net charge, their polarity and the hydrophobic nature of the interface.…”

Section: Discussionmentioning

confidence: 99%

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Structural Insights into Calcium-Bound S100P and the V Domain of the RAGE Complex

Penumutchu

Chou

2014

PLoS ONE

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The S100P protein is a member of the S100 family of calcium-binding proteins and possesses both intracellular and extracellular functions. Extracellular S100P binds to the cell surface receptor for advanced glycation end products (RAGE) and activates its downstream signaling cascade to meditate tumor growth, drug resistance and metastasis. Preventing the formation of this S100P-RAGE complex is an effective strategy to treat various disease conditions. Despite its importance, the detailed structural characterization of the S100P-RAGE complex has not yet been reported. In this study, we report that S100P preferentially binds to the V domain of RAGE. Furthermore, we characterized the interactions between the RAGE V domain and Ca2+-bound S100P using various biophysical techniques, including isothermal titration calorimetry (ITC), fluorescence spectroscopy, multidimensional NMR spectroscopy, functional assays and site-directed mutagenesis. The entropy-driven binding between the V domain of RAGE and Ca+2-bound S100P was found to lie in the micromolar range (Kd of ∼6 µM). NMR data-driven HADDOCK modeling revealed the putative sites that interact to yield a proposed heterotetrameric model of the S100P-RAGE V domain complex. Our study on the spatial structural information of the proposed protein-protein complex has pharmaceutical relevance and will significantly contribute toward drug development for the prevention of RAGE-related multifarious diseases.

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Section: Resultssupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Structural Insights into Calcium-Bound S100P and the V Domain of the RAGE Complex

Penumutchu

Chou

2014

PLoS ONE

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“…The stick structures of resides Asn-53, Leu-87, and Ala-90 of one of the S100A11 monomers (green) are shown in red. S100A6 to the RAGE V domain is located at loops 1 and 3 and helix 4 (27). For S100B, the binding region on loop 1, loop 3, helix 3, and helix 4 has been investigated to determine its interaction with the RAGE V domain (24).…”

Section: Discussionmentioning

confidence: 99%

“…Some ligands can interact with both the variable domain and constant domain simultaneously, such as S100B (24) and S100A12 protein (25,26). Furthermore, S100A6 protein can even interact with V, C1, and C2 domains (27,28). However, the mechanisms by which some S100 family proteins bind to RAGE are still shrouded in mystery.…”

mentioning

confidence: 99%

Tranilast Blocks the Interaction between the Protein S100A11 and Receptor for Advanced Glycation End Products (RAGE) V Domain and Inhibits Cell Proliferation

Huang

Chou

2016

Journal of Biological Chemistry

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The human S100 calcium-binding protein A11 (S100A11) is a member of the S100 protein family. Once S100A11 proteins bind to calcium ions at EF-hand motifs, S100A11 changes its conformation, promoting interaction with target proteins. The receptor for advanced glycation end products (RAGE) consists of three extracellular domains, including the V domain, C1 domain, and C2 domain. In this case, the V domain is the target for mutant S100A11 (mS100A11) binding. RAGE binds to the ligands, resulting in cell proliferation, cell growth, and several signal transduction cascades. We used NMR and fluorescence spectroscopy to demonstrate the interactions between mS100A11 and RAGE V domain. The tranilast molecule is a drug used for treating allergic disorders. We discovered that the RAGE V domain and tranilast would interact with mS100A11 by using 1 H-15 N HSQC NMR titrations. According to the results, we obtained two binary complex models from the HADDOCK program, S100A11-RAGE V domain and S100A11-tranilast, respectively. We overlapped two binary complex models with the same orientation of S100A11 homodimer and demonstrated that tranilast would block the binding site between S100A11 and the RAGE V domain. We further utilized a water-soluble tetrazolium-1 assay to confirm this result. We think that the results will be potentially useful in the development of new anti-cancer drugs.Human S100 proteins are a family of low molecular weight, homodimeric, and acidic proteins that contain two EF-hand motifs that can bind to calcium ions (1, 2). Human S100A11 (S100C) protein is a member of the S100 family. S100A11 was first discovered in chicken gizzards and is also called calgizzarin (3). S100A11 protein can be expressed in the heart, kidney, liver, lung, and other tissues. It is most abundant in smooth muscle tissues (4). In previous studies, it has been shown that S100A11 protein can interact with various other proteins, such as annexin A1 and A2, ATPase Rad54B, and RAGE.2 The interactions induce activities or conformational changes of these target proteins and further promote the specific physiological functions. Calcium-bound S100A11 homodimer acts as a bridge to link two N termini of annexin proteins, inducing plasma membrane vesiculation in cells (5, 6). Interaction between S100A11 and DNA repair and recombination protein Rad54B participates in the repair of double-stranded DNA and regulation of the cell cycle (7). Furthermore, S100A11-RAGE interaction is correlated with the inflammation of chondrocytes (8). It has been reported that overexpression of S100A11 protein is associated with a number of cancers, including breast (9), colon (10), pancreatic (11), and papillary thyroid carcinoma (12). However, overexpression of S100A11 protein results in the contrary effect in ovarian (13) and bladder cancer (14). Reduced expression of S100A11 protein is correlated with progression of ovarian and bladder cancer, which has been investigated in previous studies. RAGE, the receptor of the immunoglobulin for signal transductions at the cel...

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“…We showed that S100A6 could interact with both the VC1 and the C2 domain of RAGE, but that in human neuroblastoma, signaling was transduced through the C2 domain [81]. The interaction of the C3S mutant form of S100A6 with the V domain of RAGE has recently been studied in details [230]. Similarly to what we observed with S100B, S100A2 and S100A4, RAGE overexpression in the WM115 melanoma cells resulted in the up-regulation of S100A6, by the melanoma cells, when the cells were forming xenograft tumors in nude mice, compared to control tumors (Meghnani et al 2014, International Journal of Biochemistry and Cell Biology, in press).…”

Section: S100a6mentioning

confidence: 99%

RAGE and Its Ligands in Melanoma

Leclerc¹

2015

Melanoma - Current Clinical Management and Future Therapeutics

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Interaction of the S100A6 mutant (C3S) with the V domain of the receptor for advanced glycation end products (RAGE)

Cited by 32 publications

References 32 publications

Structural Insights into Calcium-Bound S100P and the V Domain of the RAGE Complex

Structural Insights into Calcium-Bound S100P and the V Domain of the RAGE Complex

Tranilast Blocks the Interaction between the Protein S100A11 and Receptor for Advanced Glycation End Products (RAGE) V Domain and Inhibits Cell Proliferation

RAGE and Its Ligands in Melanoma

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