S100B proteins that lack one or both cysteine residues can induce inflammatory responses in astrocytes and microglia

Koppal, Tanuja; Lam, Amy G.M; Guo, Ling; Eldik, Linda J. Van

doi:10.1016/s0197-0186(01)00047-x

Cited by 60 publications

(48 citation statements)

References 46 publications

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“…Analysis of the V construct in the presence of the three mutants by SDS-PAGE under non-reducing and reducing conditions confirmed that the reactive cysteine was Cys84, so the C84S mutant was used for all further experiments ( Figure S7). Notably, this cysteine to serine mutant was shown previously to be functional (55).…”

Section: S100b Binds To the V Domain Of Rage With Nm Affinitymentioning

confidence: 79%

The Extracellular Region of the Receptor for Advanced Glycation End Products Is Composed of Two Independent Structural Units

et al. 2007

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The receptor for advanced glycation end products (RAGE) is an important cell surface receptor being pursued as a therapeutic target because it has been implicated in complications arising from diabetes and chronic inflammatory conditions. RAGE is a single membrane spanning receptor containing a very small ~40 residue cytosolic domain and a large extracellular region comprised of 3 Ig-like domains. In this study, high level bacterial expression systems and purification protocols were generated for the extracellular region of RAGE (sRAGE) and the five permutations of single and tandem domain constructs to enable biophysical and structural characterization of its tertiary and quaternary structure. The structure and stability of each of these six protein constructs was assayed by biochemical methods including limited proteolysis, dynamic light scattering, CD, and NMR. A homology model of sRAGE was constructed to aid in the interpretation of the experimental data. Our results show that the V and C1 domains are not independent domains, but rather form an integrated structural unit. In contrast, C2 is attached to VC1 by a flexible linker and is fully independent. The interaction with a known RAGE ligand, Ca 2+ -S100B, was mapped to VC1, with the major contribution from the V domain but clearly defined secondary effects from the C1 domain. The implications of these results are discussed with respect to models for RAGE signaling.

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Section: S100b Binds To the V Domain Of Rage With Nm Affinitymentioning

confidence: 79%

The Extracellular Region of the Receptor for Advanced Glycation End Products Is Composed of Two Independent Structural Units

et al. 2007

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“…Previously, disulfide-linked dimer formation has been reported for S100B, a calcium-binding protein with neurotrophic and mitogenic activity (38). It was shown that this dimerization can be induced by copper (39) and that deletion or oxidation of free cysteine in S100B leads to changes in cell signaling and inflammatory response (40,41). The correlation between thiol oxidation and changes in activity are of particular interest for ASM considering the recent report (42) of a link between H 2 O 2 -induced apoptosis and the activation of ASM.…”

Section: Discussionmentioning

confidence: 98%

Activation of Human Acid Sphingomyelinase through Modification or Deletion of C-terminal Cysteine

Qiu¹,

Edmunds²,

Baker-Malcolm³

et al. 2003

Journal of Biological Chemistry

129

119

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One form of Niemann-Pick disease is caused by a deficiency in the enzymatic activity of acid sphingomyelinase. During efforts to develop an enzyme replacement therapy based on a recombinant form of human acid sphingomyelinase (rhASM), purified preparations of the recombinant enzyme were found to have substantially increased specific activity if cell harvest media were stored for several weeks at ؊20°C prior to purification. This increase in activity was found to correlate with the loss of the single free thiol on rhASM, suggesting the involvement of a cysteine residue. It was demonstrated that a variety of chemical modifications of the free cysteine on rhASM all result in substantial activation of the enzyme, and the modified cysteine responsible for this activation was shown to be the C-terminal residue (Cys 629 ). Activation was also achieved by copper-promoted dimerization of rhASM (via cysteine) and by Cterminal truncation using carboxypeptidase Y. The role of the C-terminal cysteine in activation was confirmed by creating mutant forms of rhASM in which this residue was either deleted or replaced by a serine, with both forms having substantially higher specific activity than wild-type rhASM. These results indicate that purified rhASM can be activated in vitro by loss of the free thiol on the C-terminal cysteine via chemical modification, dimerization, or deletion of this amino acid residue. This method of activation is similar to the cysteine switch mechanism described previously for matrix metalloproteinases and could represent a means of posttranslational regulation of ASM activity in vivo.

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“…In this context, S100B dimers linked together by disulfide bonds induce neurite outgrowth, but dimers without disulfide bonds can induce an inflammatory response in glial cells (49,50). Furthermore, noncovalent tetramers of S100B found in human brain extracts appear to induce RAGE multimerization (51).…”

Section: Discussionmentioning

confidence: 99%

Transamidation by Transglutaminase 2 Transforms S100A11 Calgranulin into a Procatabolic Cytokine for Chondrocytes

Cecil

Terkeltaub

2008

The Journal of Immunology

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In osteoarthritis (OA), low-grade joint inflammation promotes altered chondrocyte differentiation and cartilage catabolism. S100/calgranulins share conserved calcium-binding EF-hand domains, associate noncovalently as homodimers and heterodimers, and are secreted and bind receptor for advanced glycation end products (RAGE). Chondrocyte RAGE expression and S100A11 release are stimulated by IL-1β in vitro and increase in OA cartilage in situ. Exogenous S100A11 stimulates chondrocyte hypertrophic differentiation. Moreover, S100A11 is covalently cross-linked by transamidation catalyzed by transglutaminase 2 (TG2), itself an inflammation-regulated and redox stress-inducible mediator of chondrocyte hypertrophic differentiation. In this study, we researched mouse femoral head articular cartilage explants and knee chondrocytes, and a soluble recombinant double point mutant (K3R/Q102N) of S100A11 TG2 transamidation substrate sites. Both TG2 and RAGE knockout cartilage explants retained IL-1β responsiveness. The K3R/Q102N mutant of S100A11 retained the capacity to bind to RAGE and chondrocytes but lost the capacity to signal via the p38 MAPK pathway or induce chondrocyte hypertrophy and glycosaminoglycans release. S100A11 failed to induce hypertrophy, glycosaminoglycan release, and appearance of the aggrecanase neoepitope NITEGE in both RAGE and TG2 knockout cartilages. We conclude that transamidation by TG2 transforms S100A11 into a covalently bonded homodimer that acquires the capacity to signal through the p38 MAPK pathway, accelerate chondrocyte hypertrophy and matrix catabolism, and thereby couple inflammation with chondrocyte activation to potentially promote OA progression.

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S100B proteins that lack one or both cysteine residues can induce inflammatory responses in astrocytes and microglia

Cited by 60 publications

References 46 publications

The Extracellular Region of the Receptor for Advanced Glycation End Products Is Composed of Two Independent Structural Units

The Extracellular Region of the Receptor for Advanced Glycation End Products Is Composed of Two Independent Structural Units

Activation of Human Acid Sphingomyelinase through Modification or Deletion of C-terminal Cysteine

Transamidation by Transglutaminase 2 Transforms S100A11 Calgranulin into a Procatabolic Cytokine for Chondrocytes

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