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At least 19 recordsLinked to original sources
PubMed2004

S100 protein translocation in response to extracellular S100 is mediated by receptor for advanced glycation endproducts in human endothelial cells.

The extracellular functions of S100 proteins have attracted more attention in recent years. S100 proteins are a group of calcium-binding proteins which exhibit cell- and tissue-specific expression, and different expression levels of members from this family have been observed in various pathological conditions. The reported extracellular functions of S100 proteins include the ability to enhance neurite outgrowth, involvement in inflammation, and motility of tumour cells. In our previous study, we reported translocation of S100A13 in response to the elevated intracellular calcium levels induced by angiotensin II. In order to investigate potential effects of extracellular S100A13, recombinant S100A13 was used here to stimulate human endothelial cells. Addition of extracellular S100A13 to the cells resulted in both endogenous protein translocation and protein uptake from the extracellular space. To test specificity of this effect, addition of various other S100 proteins was also performed. Interestingly, translocation of specific S100 proteins was only observed when the cells were stimulated with the same extracellular S100 protein. Since the receptor for advanced glycation end products (RAGE) is a putative cell surface receptor for S100 proteins and is involved in various signal transduction pathways, we next investigated the interaction between the receptor and extracellular S100 proteins. We show here that NF-kappaB which is a downstream regulator in RAGE-mediated transduction pathways can be activated by addition of extracellular S100 proteins, and translocation of S100 proteins was inhibited by soluble RAGE. These experiments suggest a common cell surface receptor for S100 proteins on endothelial cells even though intracellular translocation induced by extracellular S100 proteins is specific.

Angiotensin II↗
PubMed2005

Proteins of the S100 family regulate the oligomerization of p53 tumor suppressor.

S100B protein is elevated in the brains of patients with early stages of Alzheimer's disease and Down's syndrome. S100A4 is correlated with the development of metastasis. Both proteins bind to p53 tumor suppressor. We found that both S100B and S100A4 bind to the tetramerization domain of p53 (residues 325-355) only when exposed in lower oligomerization states and so they disrupt the tetramerization of p53. In addition, S100B binds to the negative regulatory and nuclear localization domains, which results in a very tight binding to p53 protein sequences that exposed the tetramerization domain in their C terminus. Because the trafficking of p53 depends on its oligomerization state, we suggest that S100B and S100A4 could regulate the subcellular localization of p53. But, the differences in the way these proteins bind to p53 could result in S100B and S1004 having different effects on p53 function in cell-cycle control.

Amino Acid Sequence↗
PubMed2004

S100 proteins and their influence on pro-survival pathways in cancer.

The S100 gene family is composed of at least 20 members that share a common structure defined in part by the Ca2+ binding EF-hand motif. These genes which are expressed in a discriminate fashion in specific cells and tissues, have been described to have either an intracellular or extracellular function, or both. S100 proteins are implicated in the immune response, differentiation, cytoskeleton dynamics, enzyme activity, Ca2+ homeostasis and growth. A potential role for S100 proteins in neoplasia stems from these activities and from the observation that several S100 proteins have altered levels of expression in different stages and types of cancer. While the precise role and importance of S100 proteins in the development and promotion of cancer is poorly understood, it appears that the binding of Ca2+ is essential for exposing amino acid residues that are important in forming protein-protein interactions with effector molecules. The identity of some of these effector molecules has also now begun to emerge, and with this the elucidation of the signaling pathways that are modulated by these proteins. Some of these interactions are consistent with the diverse functions noted above. Others suggest that, many S100s may also promote cancer progression through specific roles in cell survival and apoptosis pathways. This review summarizes these findings and their implications.

Amino Acid Motifs↗
PubMed2001

Development and progression of malignancy in human colon tissues are correlated with expression of specific Ca(2+)-binding S100 proteins.

The expression levels of seven different S100 proteins (S100A1, S100A2, S100A3, S100A4, S100A5, S100A6, and S100B) were characterized by immunohistochemistry in the epithelial versus connective tissues of a series of 35 colon specimens, including 6 normal samples, 5 adenomas with low-grade dysplasia, 5 adenomas with high-grade dysplasia, and 19 cancers. The results showed that S100A2, S100A3, and S100B proteins could not (or only marginally) be detected in colon tissues. On the other hand, the expression of S100A6 increased in epithelial tissues directly proportional to the increase of malignancy. The percentage of epithelial (or connective tissue) cells expressing S100A4 significantly decreased as the malignancy grade increased. The expression level of S100A1 proteins was somewhat higher in the connective tissues of normal cases and adenomas with low-grade dysplasia than in adenomas with high-grade dysplasia and cancers. This pattern of expression was not observed in epithelial tissues. While the node-positive cancers did not express S100A1, about half of the node-negative specimens did. The expression levels of S100A5 were similar in different epithelial tissues. However, in the connective tissues the expression levels decreased inversely proportional to the increase in pathological grading of the specimens. Therefore, the present study implicates several S100 proteins as useful tools for histochemical typing of colon cancer malignancy development.

Adenoma↗
PubMed2002

Solution NMR structure of S100B bound to the high-affinity target peptide TRTK-12.

The solution NMR structure is reported for Ca(2+)-loaded S100B bound to a 12-residue peptide, TRTK-12, from the actin capping protein CapZ (alpha1 or alpha2 subunit, residues 265-276: TRTKIDWNKILS). This peptide was discovered by Dimlich and co-workers by screening a bacteriophage random peptide display library, and it matches exactly the consensus S100B binding sequence ((K/R)(L/I)XWXXIL). As with other S100B target proteins, a calcium-dependent conformational change in S100B is required for TRTK-12 binding. The TRTK-12 peptide is an amphipathic helix (residues W7 to S12) in the S100B-TRTK complex, and helix 4 of S100B is extended by three or four residues upon peptide binding. However, helical TRTK-12 in the S100B-peptide complex is uniquely oriented when compared to the three-dimensional structures of other S100-peptide complexes. The three-dimensional structure of the S100B-TRTK peptide complex illustrates that residues in the S100B binding consensus sequence (K4, I5, W7, I10, L11) are all involved in the S100B-peptide interface, which can explain its orientation in the S100B binding pocket and its relatively high binding affinity. A comparison of the S100B-TRTK peptide structure to the structures of apo- and Ca(2+)-bound S100B illustrates that the binding site of TRTK-12 is buried in apo-S100B, but is exposed in Ca(2+)-bound S100B as necessary to bind the TRTK-12 peptide.

Amino Acid Sequence↗
PubMed1996

Characterization of type III intermediate filament regulatory protein target epitopes: S-100 (beta and/or alpha) binds the N-terminal head domain; annexin II2-p11(2) binds the rod domain.

We have investigated the interaction of S-100 proteins (beta and/or alpha) and annexin II2-p11(2) with glial fibrillary acidic protein (GFAP) and desmin to have further information on the mechanisms whereby S-100 proteins and annexin II2-p11(2) affect assembly/disassembly of GFAP and desmin intermediate filaments (IFs). Analyses were conducted on either native IF subunits, GFAP or desmin rod domain, or headless GFAP or desmin. Our data indicate that: (i) S-100 proteins bind to GFAP and desmin N-terminal head domain; (ii) annexin II2-p11(2) binds to GFAP rod domain; (iii) annexin II2-p11(2) does not interact with desmin nor affects desmin assembly. The present data suggest that the ability of S-100 proteins to inhibit GFAP and desmin assemblies and to promote the disassembly of preformed GFAP and desmin IFs depends on occupation of a site on the N-terminal head domain of these IF subunit. It is known that the N-terminal head domain is critical for the progression from the stage of GFAP and desmin dimers/tetramers to that of large oligomers. On the other hand, the ability of annexin II2-p11(2) to stimulate GFAP assembly under conditions where this latter is normally hampered (e.g., at alkaline pH values) might depend on annexin II2-p11(2)-induced changes in the structure of GFAP rod domain, possibly as a consequence of charge modifications. By contrast, the inability of annexin II2-p11(2) to bind to desmin would depend on desmin resistance to charge modifications.

Animals↗
PubMed2005

Solution structure of zinc- and calcium-bound rat S100B as determined by nuclear magnetic resonance spectroscopy.

The EF-hand calcium-binding protein S100B also binds one zinc ion per subunit with a relatively high affinity (K(d) approximately 90 nM) [Wilder et al., (2003) Biochemistry 42, 13410-13421]. In this study, the structural characterization of zinc binding to calcium-loaded S100B was examined using high-resolution NMR techniques, including structural characterization of this complex in solution at atomic resolution. As with other S100 protein structures, the quaternary structure of Zn(2+)-Ca(2+)-bound S100B was found to be dimeric with helices H1, H1', H4, and H4' forming an X-type four-helix bundle at the dimer interface. NMR data together with mutational analyses are consistent with Zn(2+) coordination arising from His-15 and His-25 of one S100B subunit and from His-85 and Glu-89 of the other subunit. The addition of Zn(2+) was also found to extend helices H4 and H4' three to four residues similar to what was previously observed with the binding of target proteins to S100B. Furthermore, a kink in helix 4 was observed in Zn(2+)-Ca(2+)-bound S100B that is not in Ca(2+)-bound S100B. These structural changes upon Zn(2+)-binding could explain the 5-fold increase in affinity that Zn(2+)-Ca(2+)-bound S100B has for peptide targets such as the TRTK peptide versus Ca(2+)-bound S100B. There are also changes in the relative positioning of the two EF-hand calcium-binding domains and the respective helices comprising these EF-hands. Changes in conformation such as these could contribute to the order of magnitude higher affinity that S100B has for calcium in the presence of Zn(2+).

Animals↗
PubMed1986

Ions binding to S100 proteins. I. Calcium- and zinc-binding properties of bovine brain S100 alpha alpha, S100a (alpha beta), and S100b (beta beta) protein: Zn2+ regulates Ca2+ binding on S100b protein.

Flow dialysis measurements of calcium binding to bovine brain S100 alpha alpha, S100a (alpha beta), and S100b (beta beta) proteins in 20 mM Tris-HCl buffer at pH 7.5 and 8.3 revealed that S100 proteins bind specifically 4 Ca2+ eq/mol of protein dimer. The specific calcium-binding sites had, therefore, been assigned to typical amino acid sequences on the alpha and beta subunit. The protein affinity for calcium is much lower in the presence of magnesium and potassium. Potassium strongly antagonizes calcium binding on two calcium-binding sites responsible for most of the Ca2+-induced conformational changes on S100 proteins (probably site II alpha and site II beta). Zinc-binding studies in the absence of divalent cations revealed eight zinc-binding sites/mol of S100b protein dimer that we assumed to correspond to 4 zinc-binding sites/beta subunit. Zinc binding to S100b studied with UV spectroscopy methods showed that the occupation of the four higher affinity sites and the four lower affinity sites on the protein dimer were responsible for different conformational changes in S100b structure. Zinc binding on the higher affinity sites regulates calcium binding to S100b by increasing the protein affinity for calcium and decreasing the antagonistic effect of potassium on calcium binding. Zinc-binding studies on S100a and S100 alpha alpha protein showed that the Trp-containing S100 proteins bind zinc more weakly than S100b protein. Calcium-binding studies on zinc-bound S100a proved that calcium- and zinc-binding sites were distinct although there was no increase in zinc-bound S100a affinity for calcium, as in S100b protein. Finally we provide evidence that discrepancies between previously published results on the optical properties of S100b protein probably result from oxidation of the sulfhydryl groups in the protein.

Animals↗
PubMed1998

A novel mode of target recognition suggested by the 2.0 A structure of holo S100B from bovine brain.

BACKGROUND: S100B, a small acidic calcium-binding protein, is a member of the S100 protein family and is a multifunctional protein capable of binding several target molecules, such as cytoskeletal proteins and protein kinases, in a calcium-dependent manner. S100B is a homodimer of S100 beta subunits (beta beta) with a total of four calcium-binding motifs called EF hands. S100B is found abundantly in nervous tissue and has been implicated in Alzheimer's disease and Down's syndrome. Structural analysis of S100B in the calcium-bound state is required to gain a better understanding of the conformational changes that occur to S100B upon calcium binding and to elucidate the mode of recognition between S100B and its target molecules. RESULTS: We have determined the three-dimensional structure of holo S100B from bovine brain at 2.0 A resolution by X-ray diffraction. The dimeric S100B molecule is formed by non-covalent interactions between large hydrophobic surfaces on both S100 beta subunits. There are two EF-hand motifs per S100 beta subunit, each of which binds one calcium ion. We observe, in the calcium-bound structure, dramatic changes in the conformation of the terminal helices, from the compact structure in the apo form to a more extended form upon binding calcium. Following these changes, an exposed hydrophobic core, surrounded by many negatively charged residues, is revealed. Cys84 is positioned at an exposed surface of S100B, surrounded by hydrophobic residues, and could form a disulfide bond to tau protein, one of the known target molecules thought to interact with S100B in this way. CONCLUSIONS: The molecular structure of holo S100B suggests a novel mode of target recognition for the S100 family of calcium-binding proteins. Upon calcium binding, dramatic changes occur in the terminal helices of S100B, revealing a large hydrophobic surface, not observed in the apo form. It is through hydrophobic interactions and possibly a Cys84-mediated disulfide bond that S100B is thought to bind its target molecules.

Amino Acid Sequence↗
PubMed2006

Relevance of astrocytic activation to reductions of astrocytic GABAA receptors.

Although astrocytes express gamma-aminobutyric acid subtype-A (GABAA) receptors in the mature brain, GABAA receptor expression in a cultivation state remains controversial. In this study, we investigated the alteration of astrocytic GABAA receptor expression in in vitro and in vivo studies to elucidate the relevance of astrocytic activation to reductions of astrocytic GABAA receptors. The GABA-evoked Cl- current (GABAA response) in cultured astrocytes was determined by recording in the whole-cell mode using a conventional patch-clamp technique under voltage-clamp conditions. The respective amplitudes of GABAA responses on days in vitro 1, 3-5, 7-10, and 12-15 were 1019+/-97, 512+/-76, 84+/-21, and 22+/-9 pA, respectively, suggesting that the GABAA response subsequently diminished with in vitro aging. In immunohistochemical and biochemical analyses, the expression of GABAA receptor beta-subunit decreased, whereas expressions of glial fibrillary acidic protein (GFAP) and S100B, hallmarks of astrocytic activation, increased dramatically in the cultured astrocytes with in vitro aging. With the use of [3H]SR95531, a GABAA-specific ligand, at 24 h after transient focal ischemia, binding was significantly reduced in the astrocytic fractions without affecting the synaptosomal fractions, and decreases in the mRNA expression level of GABAA receptor beta-subunits were concurrently observed. Interestingly, the loss of GABAA response in cultured astrocytes was mitigated by co-culturing with neurons or treatments with monoclonal S100B antibodies. These results indicate that astrocytic GABAA receptors are reduced with in vitro aging and cerebral ischemia, presumably through the overproduction of S100B in activated astrocytes.

Aging↗
PubMed1988

Interactions between the microtubule-associated tau proteins and S100b regulate tau phosphorylation by the Ca2+/calmodulin-dependent protein kinase II.

Binding between the microtubule-associated tau protein and S100b protein was demonstrated by affinity chromatography and cross-linking experiments and was manifested in the effect of S100b on tau protein phosphorylation by protein kinase II. All three expressions of the binding showed that S100b discriminates among the four species of tau, revealing for the first time that the different kinds of tau may differ functionally. Noncovalent interaction between tau and S100b depended on the presence of Ca2+ or Zn2+ and resulted in total inhibition of tau phosphorylation by protein kinase II. In the absence of reducing agent, covalent binding studies between Cys84 beta in the carboxyl-terminal region of the S100b-beta subunit and tau proteins confirmed interactions between the two proteins. It is suggested that the homologous calcium-binding domain that characterizes the carboxyl terminus of S100 and the tubulin subunit may be responsible for the common interaction of both proteins with tau proteins. The physicochemical relationship between S100 subunits and p11, the subunit of a substrate for tyrosine kinase, and their similarity in interaction with protein kinase substrates are discussed.

Animals↗
PubMed2000

Differential localization of immunoreactive alpha- and beta-subunits of S-100 protein in feline testis.

This study investigates the differential localization of the alpha-subunit (S100-alpha) and the beta-subunit (S100-beta) of the S-100 protein in the feline testis, using immunohistochemistry with polyclonal antibodies to bovine S-100 protein (S-100) and monoclonal antibodies to bovine S100-alpha and S100-beta. Appreciable differences were observed in the cellular localization of the immunoreactivity of each subunit. S-100 was observed in the Sertoli cells, the epithelial cells of the transitional segment of the seminiferous tubules, Leydig cells and the peritubular cells of the seminiferous tubules, but was not observed in the epithelial cells of straight tubules and the rete testis or in the endothelial cells of blood and lymph vessels. S100-alpha immunoreactivity was localized in Sertoli cells, peritubular cells and the epithelial cells of the terminal segment of the tubules, whereas S100-beta immunoreactivity was localized in Leydig cells. The differential localization of the alpha- and beta-subunits of the S-100 protein in the feline testis suggests that this protein is multifunctional and be useful as an investigative tool in studying feline testis function.

Animals↗
PubMed1984

Differential localization of "brain-specific" S-100 and its subunits in rat salivary glands.

In the rat, the S-100 antigens in the submandibular gland were found to be immunochemically identical with those in the brain (glial cells) when compared using crossed immunoelectrophoresis. Specific antibodies against the S-100a non-beta and against the S-100 beta subunit were prepared from antibodies against crude S-100 protein and from S-100 components (S-100a and b) by affinity chromatography. In the rat salivary glands a differential distribution of subunit immunoreactivity was clearly evidenced using indirect immunofluorescence. Certain intercalated duct cells of the submandibular gland as well as Schwann cells contained the S-100 beta subunit immunoreactivity exclusively, while other duct cells in parotid, submandibular, and sublingual glands contained S-100a non-beta subunit immunoreactivity. Both subunits were present in astrocytes and ependymal cells. The immunocytochemical localization of alpha and beta subunits is a promising technique for the classification of various types of S-100-containing cells.

Animals↗
PubMed1987

S100a0 (alpha alpha) protein, a calcium-binding protein, is localized in the slow-twitch muscle fiber.

We previously showed that, in contrast to the distribution of S100b (beta beta), S100a0 (alpha alpha) is mainly present in human skeletal and heart muscles at the level of 1-2 micrograms/mg of soluble protein and is universally distributed at high levels in skeletal and heart muscles of various mammals. To elucidate cellular and ultrastructural localizations of the alpha subunit of S100 protein (S100-alpha) in skeletal muscle, we used immunohistochemical and enzyme immunoassay methods. The immunohistochemical study revealed that S100-alpha is mainly localized in slow-twitch muscle fibers, whereas the beta subunit of S100 protein (S100-beta) was not detected in both types of muscle fibers, an observation indicating that the predominant form of S100 protein in the slow-twitch muscle fiber is not S100a or S100b, but S100a0. The quantitative analysis using enzyme immunoassay corroborates the immunohistochemical finding: The S100-alpha concentration of mouse soleus muscle (mainly composed of slow-twitch muscle fibers) is about threefold higher than that of mouse rectus femoris muscle (mainly composed of fast-twitch muscle fibers). At the ultrastructural level, S100-alpha is associated with polysomes, sarcoplasmic reticulum, the plasma membrane, the pellicle around lipid droplets, the outer membrane of mitochondria, and thin and thick filaments, by immunoelectron microscopy.

Animals↗
PubMed1981

Structural relation of two S-100 proteins in bovine brain; subunit composition of S-100a protein.

Dodecyl sulfate/urea/polyacrylamide gel electrophoresis of S-100a protein, one of the two major components of the brain-specific S-100 protein, indicated the presence of two different subunits in the protein. These subunits (alpha and beta subunits) were purified from the aminoethylated protein by column chromatography on Sephadex G-75, and the purified subunits were subjected to analyses. The results have shown that S-100a protein is a dimer of alpha and beta subunits, with each subunit having a molecular weight of approximately 10500. Structural comparison of these subunits with the subunit of S-100b protein, the other component of S-100 protein consisting of two identical subunits with known amino acid sequence, has revealed that the beta subunit and the subunit of S-100b protein are identical, so that S-100a protein is related to S-100b protein by sharing one of the subunits as a common structural constituent.

Amino Acids↗
PubMed1983

The S100-b protein: tyrosine residues do not exhibit an abnormal fluorescence spectrum.

The beta subunit of the bovine brain S100-b protein (beta beta) lacks tryptophyl residue but contains one tyrosine. Our experiments show that this protein is characterized by a typical tyrosine fluorescence spectrum, with a maximum at 303 nm. Identical fluorescence properties were found for the rat brain S100-b protein. Comparison with the fluorescence spectrum of the bovine brain S100-a' protein (alpha'beta), which contains a tryptophan residue in the alpha' subunit, enables us to demonstrate that the recent report describing an abnormal fluorescence spectrum for the bovine brain S100-b protein may result from a contamination of the S100-b by the S100-a' protein.

Animals↗
PubMed1988

Reinvestigation of the sulfhydryl reactivity in bovine brain S100b (beta beta) protein and the microtubule-associated tau proteins. Ca2+ stimulates disulfide cross-linking between the S100b beta-subunit and the microtubule-associated tau(2) protein.

Zn2+ and Ca2+ affect the conformation of bovine brain S100b (beta beta) protein and the exposure of its Cys-84 beta. Zn2+ binding to high-affinity sites of native S100b protected the sulfhydryl groups against the thiol-specific reagent 5,5'-dithiobis(2-nitrobenzoate) and antagonized the Ca2+-stimulated reactivity of Cys-84 beta toward the reagent. Spectroscopic studies on the fluorescence properties of labeled S100b with the fluorescent probes bimane and acrylodan at Cys-84 beta confirmed the antagonistic effect of Ca2+ and Zn2+ with respect to the conformational properties of the protein. Measurements of fluorescence dynamics on bimane-labeled S100b indicated that the slow monomer-dimer equilibrium that characterizes the apoprotein at micromolar concentrations was shifted to the monomer form in the presence of Zn2+, a fact that could explain the previously reported Zn2+-dependent increase of S100b protein affinity for calcium. The difference in the effects of Ca2+ and Zn2+ on the reactivity of Cys-84 beta in S100b was confirmed when we observed that Ca2+ and Zn2+ have opposite actions on the formation of disulfide bridges between Cys-84 beta of the S100b beta-subunit and sulfhydryl groups on the microtubule-associated tau(2) protein. Ca2+ stimulated the covalent complex formation whereas Zn2+ inhibited it. We suggest that Zn2+ may have a modulatory function on Cys-84 beta reactivity in the S100b beta-subunit in vivo. Two types of divalent complexes between tau(2) and beta-subunit were formed in the presence of Ca2+, an equimolar complex tau(2)-beta 1 and a complex of one molecule of tau(2) with two beta-subunits, tau(2)-beta 2.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗