Structural and functional insights into RAGE activation by multimeric S100B

Ostendorp, Thorsten; Leclerc, Estelle; Galichet, Arnaud; Koch, Michael; Demling, Nina; Weigle, Bernd; Heizmann, Claus W.; Kroneck, Peter M. H.; Fritz, Günter

doi:10.1038/sj.emboj.7601805

Cited by 214 publications

(237 citation statements)

References 57 publications

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“…1D), in accordance with the specificity of BoxA blocking effect toward HMGB1 (60). The present results also suggested that a lack of effects of low doses of S100B on microglia migration might be dependent on the inability of S100B to displace RAGE-bound HMGB1, because HMGB1 and S100B both bind to RAGE V domain (51,62).…”

Section: S100b Stimulates Microglia Transmigration In a Rage-dependentsupporting

confidence: 86%

S100B Protein Stimulates Microglia Migration via RAGE-dependent Up-regulation of Chemokine Expression and Release

Bianchi

Kastrisianaki

Giambanco

et al. 2011

Journal of Biological Chemistry

208

173

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The Ca 2؉ -binding protein of the EF-hand type, S100B, is abundantly expressed in and secreted by astrocytes, and release of S100B from damaged astrocytes occurs during the course of acute and chronic brain disorders. Thus, the concept has emerged that S100B might act an unconventional cytokine or a damage-associated molecular pattern protein playing a role in the pathophysiology of neurodegenerative disorders and inflammatory brain diseases. S100B proinflammatory effects require relatively high concentrations of the protein, whereas at physiological concentrations S100B exerts trophic effects on neurons. Most if not all of the extracellular (trophic and toxic) effects of S100B in the brain are mediated by the engagement of RAGE (receptor for advanced glycation end products). We show here that high S100B stimulates murine microglia migration in Boyden chambers via RAGE-dependent activation of Src kinase, Ras, PI3K, MEK/ERK1/2, RhoA/ROCK, Rac1/JNK/AP-1, Rac1/ NF-B, and, to a lesser extent, p38 MAPK. Recruitment of the adaptor protein, diaphanous-1, a member of the formin protein family, is also required for S100B/RAGE-induced migration of microglia. The S100B/RAGE-dependent activation of diaphanous-1/Rac1/JNK/AP-1, Ras/Rac1/NF-B and Src/Ras/PI3K/ RhoA/diaphanous-1 results in the up-regulation of expression of the chemokines, CCL3, CCL5, and CXCL12, whose release and activity are required for S100B to stimulate microglia migration. Lastly, RAGE engagement by S100B in microglia results in up-regulation of the chemokine receptors, CCR1 and CCR5. These results suggests that S100B might participate in the pathophysiology of brain inflammatory disorders via RAGEdependent regulation of several inflammation-related events including activation and migration of microglia. S100B is a Ca 2ϩ -binding protein of the EF-hand type abundantly expressed in astrocytes (1). S100B has been implicated in the regulation of astrocyte shape, migration, proliferation and differentiation via activation of the Src/PI3K module and PI3K-dependent stimulation of Akt and RhoA activities and hence of the supramolecular organization of F-actin (2). S100B also regulates the state of assembly of microtubules and type III intermediate filaments (3) and the cytosolic Ca 2ϩ concentration (4). In addition to having intracellular regulatory activities, S100B also exerts extracellular effects. Indeed, astrocytes secrete the protein constitutively and to a larger extent under the action of several stimuli including the proinflammatory cytokine, TNF-␣ (see for review Ref. 1). Moreover, levels of brain S100B are elevated in the aging brain and in several pathological conditions such as Alzheimer disease, brain infarct, epilepsy, and infectious diseases, as well as in Down syndrome (5, 6) in consequence of S100B human gene mapping to chromosome 21q22.3 (7). For example, hypertrophic astrocytes in peri-infarct areas and in neuritic plaques in Alzheimer disease and Down syndrome show elevated expression levels of S100B, and S100B can be detected outside hypert...

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Section: S100b Stimulates Microglia Transmigration In a Rage-dependentsupporting

confidence: 86%

S100B Protein Stimulates Microglia Migration via RAGE-dependent Up-regulation of Chemokine Expression and Release

Bianchi

Kastrisianaki

Giambanco

et al. 2011

Journal of Biological Chemistry

208

173

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“…S100 family proteins are typically homodimers; however higher-order oligomers can be formed under specific conditions (20)(21)(22). As described by us previously, Ca 2þ -S100A4 dimers can assemble into a continuous superhelical arrangement due to the interaction of the C-terminal tail with the target peptide binding cleft of symmetry-related molecules (5).…”

Section: Resultsmentioning

confidence: 95%

“…Although the inactive tetramer has not been characterized structurally, the peptide is thought to induce the formation of a nonnatural tetramer (35). The recent characterization of S100B, S100A8/A9 and S100A12 as well-defined oligomers comprised of two to four S100 dimers (20)(21)(22), suggests that the propensity to form higher-order structures may be a common feature of S100 proteins. This characteristic is also shared by S100A4 as we and others demonstrated that S100A4 can form tetramers or higher-order oligomers in the absence of added compounds (5 and 36).…”

Section: Discussionmentioning

confidence: 99%

Phenothiazines inhibit S100A4 function by inducing protein oligomerization

Malashkevich

Dulyaninova

Ramagopal

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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S100A4, a member of the S100 family of Ca 2þ -binding proteins, regulates carcinoma cell motility via interactions with myosin-IIA. Numerous studies indicate that S100A4 is not simply a marker for metastatic disease, but rather has a direct role in metastatic progression. These observations suggest that S100A4 is an excellent target for therapeutic intervention. Using a unique biosensorbased assay, trifluoperazine (TFP) was identified as an inhibitor that disrupts the S100A4/myosin-IIA interaction. To examine the interaction of S100A4 with TFP, we determined the 2.3 Å crystal structure of human Ca 2þ -S100A4 bound to TFP. Two TFP molecules bind within the hydrophobic target binding pocket of Ca 2þ -S100A4 with no significant conformational changes observed in the protein upon complex formation. NMR chemical shift perturbations are consistent with the crystal structure and demonstrate that TFP binds to the target binding cleft of S100A4 in solution. Remarkably, TFP binding results in the assembly of five Ca 2þ -S100A4/TFP dimers into a tightly packed pentameric ring. Within each pentamer most of the contacts between S100A4 dimers occurs through the TFP moieties. The Ca 2þ -S100A4/prochlorperazine (PCP) complex exhibits a similar pentameric assembly. Equilibrium sedimentation and cross-linking studies demonstrate the cooperative formation of a similarly sized S100A4/TFP oligomer in solution. Assays examining the ability of TFP to block S100A4-mediated disassembly of myosin-IIA filaments demonstrate that significant inhibition of S100A4 function occurs only at TFP concentrations that promote S100A4 oligomerization. Together these studies support a unique mode of inhibition in which phenothiazines disrupt the S100A4/ myosin-IIA interaction by sequestering S100A4 via small molecule-induced oligomerization.calcium | X-ray crystallography | NMR | small molecule inhibitor | metastasis T he S100 proteins, of which there are more than 20 members, are characterized by their solubility in 100% saturated ammonium sulfate (1 and 2). Each S100 family member contains two Ca 2þ -binding loops; a C-terminal "typical" EF-hand comprised of 12 residues and an N-terminal pseudo EF-hand consisting of 14 residues. The basic organization of the S100 proteins is a symmetric, antiparallel homodimer, in which the N-and C-terminal helices (helices 1 and 4) from each subunit interact to form a stable four helix bundle that serves as the dimer interface. Calcium binding to the C-terminal typical EF-hand significantly alters the angle between helices 3 and 4, which flank the C-terminal Ca 2þ -binding loop, and exposes a hydrophobic cleft that constitutes a binding surface for target proteins (3-5). Thus the S100 proteins operate as calcium-activated switches that bind and regulate the activity of diverse protein targets. S100 proteins are expressed in a tissue and cell specific manner. Elevated expression of individual family members is associated with a number of human pathologies, including cardiomyopathies, cancer, neurodegeneration, and in...

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“…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%

Specific Citrullination Causes Assembly of a Globular S100A3 Homotetramer

Kizawa¹,

Takahara

Troxler

et al. 2008

Journal of Biological Chemistry

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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.

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Structural and functional insights into RAGE activation by multimeric S100B

Cited by 214 publications

References 57 publications

S100B Protein Stimulates Microglia Migration via RAGE-dependent Up-regulation of Chemokine Expression and Release

S100B Protein Stimulates Microglia Migration via RAGE-dependent Up-regulation of Chemokine Expression and Release

Phenothiazines inhibit S100A4 function by inducing protein oligomerization

Specific Citrullination Causes Assembly of a Globular S100A3 Homotetramer

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