Hexameric Calgranulin C (S100A12) Binds to the Receptor for Advanced Glycated End Products (RAGE) Using Symmetric Hydrophobic Target-binding Patches

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207

S100 proteins are EF-hand calcium-binding proteins with various intracellular functions including cell proliferation, differentiation, migration, and apoptosis. Some S100 proteins are also secreted and exert extracellular paracrine and autocrine functions. Experimental results suggest that the receptor for advanced glycation end products (RAGE) plays important roles in mediating S100 protein-induced cellular signaling. Here we compared the interaction of two S100 proteins, S100B and S100A6, with RAGE by in vitro assay and in culture of human SH-SY5Y neuroblastoma cells. Our in vitro binding data showed that S100B and S100A6, although structurally very similar, interact with different RAGE extracellular domains. Our cell assay data demonstrated that S100B and S100A6 differentially modulate cell survival. At micromolar concentration, S100B increased cellular proliferation, whereas at the same concentration, S100A6 triggered apoptosis. Although both S100 proteins induced the formation of reactive oxygen species, S100B recruited phosphatidylinositol 3-kinase/AKT and NF-B, whereas S100A6 activated JNK. More importantly, we showed that S100B and S100A6 modulate cell survival in a RAGE-dependent manner; S100B specifically interacted with the RAGE V and C 1 domains and S100A6 specifically interacted with the C 1 and C 2 RAGE domains. Altogether these results highlight the complexity of S100/RAGE cellular signaling.

Section: Resultsmentioning

confidence: 99%

S100B and S100A6 Differentially Modulate Cell Survival by Interacting with Distinct RAGE (Receptor for Advanced Glycation End Products) Immunoglobulin Domains

Leclerc

Fritz

Weibel

et al. 2007

237

207

“…Its hemispheric structure resulted in a slightly larger apparent molecular mass (28 kDa) than the calculated mass (23.4 kDa). Since the tetramer dissociated to the dimer at Ca 2ϩ concentrations below 1 mM (data not shown) or upon the addition of EGTA in the elution buffer, it is apparent that S100A3 tetramerized in a Ca 2ϩ -dependent manner similarly to the S100A8/S100A9 heterotetramer (5) and S100A12 hexamer (6).…”

Section: Citrullinated S100a3 Derived From Hair Follicles Andmentioning

confidence: 93%

“…They are also associated with human diseases, including inflammation, brain disorders, cancer, diabetes, heart failure, and pathological conditions of the skin and hair follicle. The basic structural and functional unit of most S100 proteins was previously thought to be a noncovalently associated antiparallel dimer; however, there is increasing evidence that some members assemble into higher order oligomers, thereby conferring their biological function (3)(4)(5)(6)(7).…”

mentioning

confidence: 99%

“…Larger assemblies than dimers have been reported for S100A2 (29), S100A4 (3, 4), S100A8/S100A9 (5, 30 -32), S100A12 (6,33), and S100B (7); however, little information is available regarding their molecular entities and natural assembly processes. The present investigation has revealed that specific arginine conversion catalyzed by a Ca 2ϩ -dependent PAD enzyme promotes S100A3 tetramerization and thereby confers its potential Ca 2ϩ -binding property.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Specific Citrullination Causes Assembly of a Globular S100A3 Homotetramer

Kizawa¹,

Takahara

Troxler

et al. 2008

S100A3 is a unique member of the Ca 2؉ -binding S100 protein family with the highest cysteine content and affinity for Zn 2؉ . This protein is highly expressed in the differentiating cuticular cells within the hair follicle and organized into mature hair cuticles. Previous studies suggest a close association of S100A3 with epithelial differentiation, leading to hair shaft formation, but its molecular function is still unknown. By two-dimensional PAGE-Western blot analyses using a modified citrulline antibody, we discovered that more than half of the arginine residues of native S100A3 are progressively converted to citrullines by Ca 2؉ -dependent peptidylarginine deiminases. Confocal immunofluorescent microscopy showed that the cytoplasmic S100A3 within the cuticular layer is mostly co-localized with the type III isoform of peptidylarginine deiminase (PAD3) but not with PAD1. Recombinant PAD1 and PAD2 are capable of converting all 4 arginines in recombinant S100A3, whereas PAD3 specifically converts only Arg-51 into citrulline. Gel filtration analyses showed that either enzymatic conversion of Arg-51 in S100A3 to citrulline or its mutational substitution with alanine (R51A) promotes a homotetramer assembly. Fluorescent titration of R51A suggested that its potential Ca 2؉ binding property increased during tetramerization. A prototype structural model of the globular Ca 2؉ -bound S100A3 tetramer with citrulline residues is presented. High concentrations of S100A3 homotetramer might provide the millimolar level of Ca 2؉ required for hair cuticular barrier formation.

“…The variable domain is predominantly related to ligand binding, such as that seen in most S100 family proteins (18), advanced glycation end products (19,20), amyloid-␤ protein (21), and amphoterin (HMGB1 (high mobility group protein 1)) (22,23). 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).…”

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

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...