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Johannes Roth - One of the best experts on this subject based on the ideXlab platform.
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01 03 ttp S100A9 deficient mice promote a tnf dependent psoriatic arthritis phenotype triggered by the bacterial environment
Annals of the Rheumatic Diseases, 2017Co-Authors: Athanasios Stratis, Johannes Roth, Thomas Vogl, Mareike Frohling, Karin Loser, Peter Paruzel, Perry J Blackshear, Debbie Stumpo, Thomas PapAbstract:Background Psoriatic-Arthritis (PsA) is a type of inflammatory chronic arthritis with a seronegative spondyloarthropathy and associated psoriasis. The Danger-Associated Molecular Pattern molecules (DAMPs) S100A8 and S100A9 are both antimicrobial proteins with chemotactic activity and are the most abundant DAMPs expressed during many inflammatory disorders. The expression of the S100A8/S100A9-complex is highly elevated in psoriasis and psoriatic arthritis. However, the mechanisms that regulate S100A8/S100A9-complex-activities are poorly understood, which has led us to examine the role of S100A8 and S100A9 under chronic inflammatory conditions. Material and methods We crossed S100A9-deficient mice with TTP (tristetraprolin)-deficient mice into a systemic inflammatory model featuring high levels of TNF with an arthritic joint destruction phenotype. Disease progression in TTP-/- x S100A9-/- mice was analysed by immunostaining, immunohistochemistry and the adapted PASI-score. To neutralise TNF in TTP-/- x S100A9-/- mice we used an aTNF-inhibiting monoclonal antibody already in clinical use for therapy of arthritis and psoriasis. To measure altered protein levels we used Western blot analysis. Primary keratinocytes were isolated of the skin from newborn mice and infected with E.coli isolated from the faeces of mice. Results TTP/S100A9 deficiency led to highly elevated levels of the S100A9 complex partner S100A8 in the epidermis and to a severe psoriatic phenotype of TTP-/- x S100A9-/- mice. Furthermore the mice showed an accelerated course of arthritis compared to TTP-/- mice, including increased articular cartilage loss and bone destruction. Inhibition of TNF by application of anti-TNF clearly reduced the psoriatic phenotype of TTP-/- x S100A9-/- mice. Additionally, the reduction of the environmental bacterial levels led to a milder phenotype and decelerated pathogenesis. The in vitro infection of isolated keratinocytes with isolated E.coli resulted in a high expression of S100A8. Conclusions The data reveal that the S100A8/S100A9-complex acts not only as a systemic danger signal molecule, but is also TNF dependent and is essential for the regulation of inflammation. The loss of S100A9 led to a disregulated inflammatory response and this to a severe psoriasis with enhanced cartilage and bone destruction. Furthermore, an exogenic bacterial factor, such as E. coli, is also demonstrated to be important in the activation of the disease.
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alarmin S100A9 induces proinflammatory and catabolic effects predominantly in the m1 macrophages of human osteoarthritic synovium
The Journal of Rheumatology, 2016Co-Authors: Martijn H J Van Den Bosch, R.f. Schelbergen, Johannes Roth, Thomas J. Vogl, A B Blom, Marije I Koenders, Fons A J Van De Loo, Wim B Van Den Berg, Peter M Van Der Kraan, Peter L E M Van LentAbstract:Objective. The alarmins S100A8 and S100A9 have been shown to regulate synovial activation, cartilage damage, and osteophyte formation in osteoarthritis (OA). Here we investigated the effect of S100A9 on the production of proinflammatory cytokines and matrix metalloprotease (MMP) in OA synovium, granulocyte macrophage colony-stimulating factor (GM-CSF)-differentiated/macrophage colony-stimulating factor (M-CSF)-differentiated macrophages, and OA fibroblasts. Methods. We determined which cell types in the synovium produced S100A8 and S100A9. Further, the production of proinflammatory cytokines and MMP, and the activation of canonical Wnt signaling, was determined in human OA synovium, OA fibroblasts, and monocyte-derived macrophages following stimulation with S100A9. Results. We observed that S100A8 and S100A9 were mainly produced by GM-CSF–differentiated macrophages present in the synovium, and to a lesser extent by M-CSF–differentiated macrophages, but not by fibroblasts. S100A9 stimulation of OA synovial tissue increased the production of the proinflammatory cytokines interleukin (IL) 1β, IL-6, IL-8, and tumor necrosis factor-α. Additionally, various MMP were upregulated after S100A9 stimulation. Experiments to determine which cell type was responsible for these effects revealed that mainly stimulation of GM-CSF–differentiated macrophages and to a lesser extent M-CSF-differentiated macrophages with S100A9 increased the expression of these proinflammatory cytokines and MMP. In contrast, stimulation of fibroblasts with S100A9 did not affect their expression. Finally, stimulation of GM-CSF–differentiated, but not M-CSF–differentiated macrophages with S100A9 activated canonical Wnt signaling, whereas incubation of OA synovium with the S100A9 inhibitor paquinimod reduced the activation of canonical Wnt signaling. Conclusion. Predominantly mediated by M1-like macrophages, the alarmin S100A9 stimulates the production of proinflammatory and catabolic mediators and activates canonical Wnt signaling in OA synovium.
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a1 30 a key role of S100A9 in the pathogenesis of psoriatic arthritis in ttp s100 deficient mice
Annals of the Rheumatic Diseases, 2016Co-Authors: Mareike Frohling, Johannes Roth, Thomas Vogl, Karin Loser, Peter Paruzel, Perry J Blackshear, Debbie Stumpo, Thomas Pap, Athanasios StratisAbstract:Background and objectives Psoriatic-Arthritis (PsA) is a type of inflammatory chronic arthritis with a seronegative spondyloarthropathy and associated psoriasis. The S100 calcium-binding molecules S100A8 and S100A9, known as damage-associated molecular pattern molecules (DAMP), are highly increased during many inflammatory disorders and their expression correlates with the severity of disease. S100A8 and S100A9 are expressed in low levels in normal epidermis, but are highly expressed in psoriasis. Interestingly a high expression of epidermal S100A8/S100A9 is also an early marker found in patients suffering from systemic onset of juvenile idiopathic arthritis, which has led us to investigate the role of DAMPs under chronic inflammatory conditions. Material and methods To analyse the role S100A8 and S100A9 have during inflammation, we crossed S100A9-deficient mice withTTP (tristetraprolin)-deficient mice as a systemic inflammatory model featuring high levels of TNF. Disease progression in TTP-/- x S100A9-/- mice was analysed by immunostaining, immunhistochemistry and the adapted PASI-score. RNA was extracted from snap-frozen mouse tissue for Real-time quantitative PCR analysis. To neutralise TNF in TTP-/- x S100A9-/- mice we used an aTNF-inhibitor monoclonal antibody already in clinical use for therapy of arthritis and psoriasis. To measure altered protein levels we used Western blot analysis. Results The loss of S100A9 in TTP-deficient mice leads to highly elevated amounts of S100A8 in the epidermis and furthermore to a severe psoriasis-like phenotype at postnatal day 8. The expression of other effector molecules in the TTP -/- /S100A9 -/- mice know to be involved in the pathogenesis of psoriasis, incuding IL-17, IL-23 and IL-22 is markedly increased compared to TTP -/- mice. Treatment withanti-TNF preventedthe mice from developing the psoriatic phenotype, indicating that the psoriasis-like skin disease of TTP -/- /S100A9 -/- mice is tumour necrosis factor (TNF) dependent. Conclusions Our results demonstrate that under inflammatory conditions, S100A9 is essential for the regulation of inflammation, suggesting that S100A9 released from epidermal cells may act not only as a systemic danger signal that is involved in the initiation of inflammatory disorders like psoriasis and arthritis, but may also have a homeostatic anti-inflammatory function in the skin.
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alarmins s100a8 S100A9 aggravate osteophyte formation in experimental osteoarthritis and predict osteophyte progression in early human symptomatic osteoarthritis
Annals of the Rheumatic Diseases, 2016Co-Authors: R.f. Schelbergen, W. De Munter, M.h. Van Den Bosch, Annet W. Sloetjes, Johannes Roth, Thomas Vogl, W.b. Van Den Berg, Peter M Van Der Kraan, Floris P J G Lafeber, Arjen B. BlomAbstract:OBJECTIVE: Alarmins S100A8 and S100A9 are major products of activated macrophages regulating cartilage damage and synovial activation during murine and human osteoarthritis (OA). In the current study, we investigated whether S100A8 and S100A9 are involved in osteophyte formation during experimental OA and whether S100A8/A9 predicts osteophyte progression in early human OA. METHODS: OA was elicited in S100A9-/- mice in two experimental models that differ in degree of synovial activation. Osteophyte size, S100A8, S100A9 and VDIPEN neoepitope was measured histologically. Chondrogenesis was induced in murine mesenchymal stem cells in the presence of S100A8. Levels of S100A8/A9 were determined in plasma of early symptomatic OA participants of the Cohort Hip and Cohort Knee (CHECK) cohort study and osteophytes measured after 2 and 5 years. RESULTS: Osteophyte size was drastically reduced in S100A9-/- mice in ligaments and at medial femur and tibia on days 21 and 42 of collagenase-induced OA, in which synovial activation is high. In contrast, osteophyte size was not reduced in S100A9-/- mice during destabilised medial meniscus OA, in which synovial activation is scant. S100A8 increased expression and activation of matrix metalloproteinases during micromass chondrogenesis, thereby possibly increasing cartilage matrix remodelling allowing for larger osteophytes. Interestingly, early symptomatic OA participants of the CHECK study with osteophyte progression after 2 and 5 years had elevated S100A8/A9 plasma levels at baseline, while C-reactive protein, erythrocyte sedimentation rate and cartilage oligomeric matrix protein were not elevated at baseline. CONCLUSIONS: S100A8/A9 aggravate osteophyte formation in experimental OA with high synovial activation and may be used to predict osteophyte progression in early symptomatic human OA.
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the calcium binding protein complex s100a8 a9 has a crucial role in controlling macrophage mediated renal repair following ischemia reperfusion
Kidney International, 2015Co-Authors: Mark C Dessing, Thomas Vogl, Alessandra Tammaro, Wilco P Pulskens, Gwendoline J D Teske, Loes M Butter, Nike Claessen, Marco Van Eijk, Tom Van Der Poll, Johannes RothAbstract:Upon ischemia/reperfusion (I/R)-induced injury, several damage-associated molecular patterns are expressed including the calcium-binding protein S100A8/A9 complex. S100A8/A9 can be recognized by Toll-like receptor-4 and its activation is known to deleteriously contribute to renal I/R-induced injury. To further test this, wild-type and S100A9 knockout mice (deficient for S100A8/A9 complex) were subjected to renal I/R. The expression of S100A8/A9 was significantly increased 1 day after I/R and was co-localized with Ly6G (mouse neutrophil marker)-positive cells. These knockout mice displayed similar renal dysfunction and damage and neutrophil influx compared with wild-type mice at this early time point. Interestingly, S100A9 knockout mice displayed altered tissue repair 5 and 10 days post I/R, as reflected by increased renal damage, sustained inflammation, induction of fibrosis, and increased expression of collagens. This coincided with enhanced expression of alternatively activated macrophage (M2) markers, while the expression of classically activated macrophage (M1) markers was comparable. Similarly, S100A9 deficiency affected M2, but not M1 macrophage polarization in vitro. During the repair phase following acute kidney injury, S100A9 deficiency affects M2 macrophages in mice leading to renal fibrosis and damage. Thus, S100A8/A9 plays a crucial part in controlling macrophage-mediated renal repair following I/R.
Thomas Vogl - One of the best experts on this subject based on the ideXlab platform.
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autoinhibitory regulation of s100a8 S100A9 alarmin activity locally restricts sterile inflammation
Journal of Clinical Investigation, 2018Co-Authors: Thomas Vogl, Athanasios Stratis, Viktor Wixler, Tom Voller, Sumita Thurainayagam, Selina K Jorch, Stefanie Zenker, Alena Dreiling, Deblina Chakraborty, Mareike FrohlingAbstract:Autoimmune diseases, such as psoriasis and arthritis, show a patchy distribution of inflammation despite systemic dysregulation of adaptive immunity. Thus, additional tissue-derived signals, such as danger-associated molecular patterns (DAMPs), are indispensable for manifestation of local inflammation. S100A8/S100A9 complexes are the most abundant DAMPs in many autoimmune diseases. However, regulatory mechanisms locally restricting DAMP activities are barely understood. We now unravel for the first time, to our knowledge, a mechanism of autoinhibition in mice and humans restricting S100-DAMP activity to local sites of inflammation. Combining protease degradation, pull-down assays, mass spectrometry, and targeted mutations, we identified specific peptide sequences within the second calcium-binding EF-hands triggering TLR4/MD2-dependent inflammation. These binding sites are free when S100A8/S100A9 heterodimers are released at sites of inflammation. Subsequently, S100A8/S100A9 activities are locally restricted by calcium-induced (S100A8/S100A9)2 tetramer formation hiding the TLR4/MD2-binding site within the tetramer interphase, thus preventing undesirable systemic effects. Loss of this autoinhibitory mechanism in vivo results in TNF-α-driven fatal inflammation, as shown by lack of tetramer formation in crossing S100A9-/- mice with 2 independent TNF-α-transgene mouse strains. Since S100A8/S100A9 is the most abundant DAMP in many inflammatory diseases, specifically blocking the TLR4-binding site of active S100 dimers may represent a promising approach for local suppression of inflammatory diseases, avoiding systemic side effects.
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pathogenic role of the damage associated molecular patterns s100a8 and S100A9 in coxsackievirus b3 induced myocarditis
Circulation-heart Failure, 2017Co-Authors: Irene Muller, Thomas Vogl, Kathleen Pappritz, Kapka Miteva, Konstantinos Savvatis, David Rohde, Patrick Most, Dirk Lassner, Burkert Pieske, Uwe KuhlAbstract:Background: The alarmins S100A8 and S100A9 are damage-associated molecular patterns, which play a pivotal role in cardiovascular diseases, inflammation, and viral infections. We aimed to investigate their role in Coxsackievirus B3 (CVB3)–induced myocarditis. Methods and Results: S100A8 and S100A9 mRNA expression was 13.0-fold ( P =0.012) and 5.1-fold ( P =0.038) higher in endomyocardial biopsies from patients with CVB3-positive myocarditis compared with controls, respectively. Elimination of CVB3 led to a downregulation of these alarmins. CVB3-infected mice developed an impaired left ventricular function and displayed an increased left ventricular S100A8 and S100A9 protein expression versus controls. In contrast, CVB3-infected S100A9 knockout mice, which are also a complete knockout for S100A8 on protein level, showed an improved left ventricular function, which was associated with a reduced cardiac inflammatory and oxidative response, and lower CVB3 copy number compared with wild-type CVB3 mice. Exogenous application of S100A8 to S100A9 knockout CVB3 mice induced a severe myocarditis similar to wild-type CVB3 mice. In CVB3-infected HL-1 cells, S100A8 and S100A9 enhanced oxidative stress and CVB3 copy number compared with unstimulated infected cells. In CVB3-infected RAW macrophages, both alarmins increased MIP-2 (macrophage inflammatory protein-2) chemokine expression, which was reduced in CVB3 S100A8 knockdown versus scrambled siRNA CVB3 cells. Conclusions: S100A8 and S100A9 aggravate CVB3-induced myocarditis and might serve as therapeutic targets in inflammatory cardiomyopathies.
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01 03 ttp S100A9 deficient mice promote a tnf dependent psoriatic arthritis phenotype triggered by the bacterial environment
Annals of the Rheumatic Diseases, 2017Co-Authors: Athanasios Stratis, Johannes Roth, Thomas Vogl, Mareike Frohling, Karin Loser, Peter Paruzel, Perry J Blackshear, Debbie Stumpo, Thomas PapAbstract:Background Psoriatic-Arthritis (PsA) is a type of inflammatory chronic arthritis with a seronegative spondyloarthropathy and associated psoriasis. The Danger-Associated Molecular Pattern molecules (DAMPs) S100A8 and S100A9 are both antimicrobial proteins with chemotactic activity and are the most abundant DAMPs expressed during many inflammatory disorders. The expression of the S100A8/S100A9-complex is highly elevated in psoriasis and psoriatic arthritis. However, the mechanisms that regulate S100A8/S100A9-complex-activities are poorly understood, which has led us to examine the role of S100A8 and S100A9 under chronic inflammatory conditions. Material and methods We crossed S100A9-deficient mice with TTP (tristetraprolin)-deficient mice into a systemic inflammatory model featuring high levels of TNF with an arthritic joint destruction phenotype. Disease progression in TTP-/- x S100A9-/- mice was analysed by immunostaining, immunohistochemistry and the adapted PASI-score. To neutralise TNF in TTP-/- x S100A9-/- mice we used an aTNF-inhibiting monoclonal antibody already in clinical use for therapy of arthritis and psoriasis. To measure altered protein levels we used Western blot analysis. Primary keratinocytes were isolated of the skin from newborn mice and infected with E.coli isolated from the faeces of mice. Results TTP/S100A9 deficiency led to highly elevated levels of the S100A9 complex partner S100A8 in the epidermis and to a severe psoriatic phenotype of TTP-/- x S100A9-/- mice. Furthermore the mice showed an accelerated course of arthritis compared to TTP-/- mice, including increased articular cartilage loss and bone destruction. Inhibition of TNF by application of anti-TNF clearly reduced the psoriatic phenotype of TTP-/- x S100A9-/- mice. Additionally, the reduction of the environmental bacterial levels led to a milder phenotype and decelerated pathogenesis. The in vitro infection of isolated keratinocytes with isolated E.coli resulted in a high expression of S100A8. Conclusions The data reveal that the S100A8/S100A9-complex acts not only as a systemic danger signal molecule, but is also TNF dependent and is essential for the regulation of inflammation. The loss of S100A9 led to a disregulated inflammatory response and this to a severe psoriasis with enhanced cartilage and bone destruction. Furthermore, an exogenic bacterial factor, such as E. coli, is also demonstrated to be important in the activation of the disease.
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a1 30 a key role of S100A9 in the pathogenesis of psoriatic arthritis in ttp s100 deficient mice
Annals of the Rheumatic Diseases, 2016Co-Authors: Mareike Frohling, Johannes Roth, Thomas Vogl, Karin Loser, Peter Paruzel, Perry J Blackshear, Debbie Stumpo, Thomas Pap, Athanasios StratisAbstract:Background and objectives Psoriatic-Arthritis (PsA) is a type of inflammatory chronic arthritis with a seronegative spondyloarthropathy and associated psoriasis. The S100 calcium-binding molecules S100A8 and S100A9, known as damage-associated molecular pattern molecules (DAMP), are highly increased during many inflammatory disorders and their expression correlates with the severity of disease. S100A8 and S100A9 are expressed in low levels in normal epidermis, but are highly expressed in psoriasis. Interestingly a high expression of epidermal S100A8/S100A9 is also an early marker found in patients suffering from systemic onset of juvenile idiopathic arthritis, which has led us to investigate the role of DAMPs under chronic inflammatory conditions. Material and methods To analyse the role S100A8 and S100A9 have during inflammation, we crossed S100A9-deficient mice withTTP (tristetraprolin)-deficient mice as a systemic inflammatory model featuring high levels of TNF. Disease progression in TTP-/- x S100A9-/- mice was analysed by immunostaining, immunhistochemistry and the adapted PASI-score. RNA was extracted from snap-frozen mouse tissue for Real-time quantitative PCR analysis. To neutralise TNF in TTP-/- x S100A9-/- mice we used an aTNF-inhibitor monoclonal antibody already in clinical use for therapy of arthritis and psoriasis. To measure altered protein levels we used Western blot analysis. Results The loss of S100A9 in TTP-deficient mice leads to highly elevated amounts of S100A8 in the epidermis and furthermore to a severe psoriasis-like phenotype at postnatal day 8. The expression of other effector molecules in the TTP -/- /S100A9 -/- mice know to be involved in the pathogenesis of psoriasis, incuding IL-17, IL-23 and IL-22 is markedly increased compared to TTP -/- mice. Treatment withanti-TNF preventedthe mice from developing the psoriatic phenotype, indicating that the psoriasis-like skin disease of TTP -/- /S100A9 -/- mice is tumour necrosis factor (TNF) dependent. Conclusions Our results demonstrate that under inflammatory conditions, S100A9 is essential for the regulation of inflammation, suggesting that S100A9 released from epidermal cells may act not only as a systemic danger signal that is involved in the initiation of inflammatory disorders like psoriasis and arthritis, but may also have a homeostatic anti-inflammatory function in the skin.
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alarmins s100a8 S100A9 aggravate osteophyte formation in experimental osteoarthritis and predict osteophyte progression in early human symptomatic osteoarthritis
Annals of the Rheumatic Diseases, 2016Co-Authors: R.f. Schelbergen, W. De Munter, M.h. Van Den Bosch, Annet W. Sloetjes, Johannes Roth, Thomas Vogl, W.b. Van Den Berg, Peter M Van Der Kraan, Floris P J G Lafeber, Arjen B. BlomAbstract:OBJECTIVE: Alarmins S100A8 and S100A9 are major products of activated macrophages regulating cartilage damage and synovial activation during murine and human osteoarthritis (OA). In the current study, we investigated whether S100A8 and S100A9 are involved in osteophyte formation during experimental OA and whether S100A8/A9 predicts osteophyte progression in early human OA. METHODS: OA was elicited in S100A9-/- mice in two experimental models that differ in degree of synovial activation. Osteophyte size, S100A8, S100A9 and VDIPEN neoepitope was measured histologically. Chondrogenesis was induced in murine mesenchymal stem cells in the presence of S100A8. Levels of S100A8/A9 were determined in plasma of early symptomatic OA participants of the Cohort Hip and Cohort Knee (CHECK) cohort study and osteophytes measured after 2 and 5 years. RESULTS: Osteophyte size was drastically reduced in S100A9-/- mice in ligaments and at medial femur and tibia on days 21 and 42 of collagenase-induced OA, in which synovial activation is high. In contrast, osteophyte size was not reduced in S100A9-/- mice during destabilised medial meniscus OA, in which synovial activation is scant. S100A8 increased expression and activation of matrix metalloproteinases during micromass chondrogenesis, thereby possibly increasing cartilage matrix remodelling allowing for larger osteophytes. Interestingly, early symptomatic OA participants of the CHECK study with osteophyte progression after 2 and 5 years had elevated S100A8/A9 plasma levels at baseline, while C-reactive protein, erythrocyte sedimentation rate and cartilage oligomeric matrix protein were not elevated at baseline. CONCLUSIONS: S100A8/A9 aggravate osteophyte formation in experimental OA with high synovial activation and may be used to predict osteophyte progression in early symptomatic human OA.
Arne Skerra - One of the best experts on this subject based on the ideXlab platform.
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the crystal structure of the human s100a8 S100A9 2 heterotetramer calprotectin illustrates how conformational changes of interacting α helices can determine specific association of two ef hand proteins
Journal of Molecular Biology, 2007Co-Authors: Ingo P Korndorfer, Florian Brueckner, Arne SkerraAbstract:Abstract The EF-hand proteins S100A8 and S100A9 are important calcium signalling proteins that are involved in wound healing and provide clinically relevant markers of inflammatory processes, such as rheumatoid arthritis and inflammatory bowel disease. Both can form homodimers via distinct modes of association, probably of lesser stability in the case of S100A9, whereas in the presence of calcium S100A8 and S100A9 associate to calprotectin, the physiologically active heterooligomer. Here we describe the crystal structure of the (S100A8/S100A9)2 heterotetramer at 1.8 A resolution. Its quaternary structure illustrates how specific heteroassociation is energetically driven by a more extensive burial of solvent accessible surface areas in both proteins, most pronounced for S100A9, thus leading to a dimer of heterodimers. A major contribution to tetramer association is made by the canonical calcium binding loops in the C-terminal halves of the two proteins. The mode of heterodimerisation in calprotectin more closely resembles the subunit association previously observed in the S100A8 homodimer and provides trans stabilisation for S100A9, which manifests itself in a significantly elongated C-terminal α-helix in the latter. As a consequence, two different putative zinc binding sites emerge at the S100A8/S100A9 subunit interface. One of these corresponds to a high affinity arrangement of three His residues and one Asp side-chain, which is unique to the heterotetramer. This structural feature explains the well known Zn2+ binding activity of calprotectin, whose overexpression can cause strong dysregulation of zinc homeostasis with severe clinical symptoms.
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the crystal structure of the human s100a8 S100A9 2 heterotetramer calprotectin illustrates how conformational changes of interacting alpha helices can determine specific association of two ef hand proteins
Journal of Molecular Biology, 2007Co-Authors: Ingo P Korndorfer, Florian Brueckner, Arne SkerraAbstract:The EF-hand proteins S100A8 and S100A9 are important calcium signalling proteins that are involved in wound healing and provide clinically relevant markers of inflammatory processes, such as rheumatoid arthritis and inflammatory bowel disease. Both can form homodimers via distinct modes of association, probably of lesser stability in the case of S100A9, whereas in the presence of calcium S100A8 and S100A9 associate to calprotectin, the physiologically active heterooligomer. Here we describe the crystal structure of the (S100A8/S100A9)(2) heterotetramer at 1.8 A resolution. Its quaternary structure illustrates how specific heteroassociation is energetically driven by a more extensive burial of solvent accessible surface areas in both proteins, most pronounced for S100A9, thus leading to a dimer of heterodimers. A major contribution to tetramer association is made by the canonical calcium binding loops in the C-terminal halves of the two proteins. The mode of heterodimerisation in calprotectin more closely resembles the subunit association previously observed in the S100A8 homodimer and provides trans stabilisation for S100A9, which manifests itself in a significantly elongated C-terminal alpha-helix in the latter. As a consequence, two different putative zinc binding sites emerge at the S100A8/S100A9 subunit interface. One of these corresponds to a high affinity arrangement of three His residues and one Asp side-chain, which is unique to the heterotetramer. This structural feature explains the well known Zn(2+) binding activity of calprotectin, whose overexpression can cause strong dysregulation of zinc homeostasis with severe clinical symptoms.
Ingo P Korndorfer - One of the best experts on this subject based on the ideXlab platform.
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the crystal structure of the human s100a8 S100A9 2 heterotetramer calprotectin illustrates how conformational changes of interacting α helices can determine specific association of two ef hand proteins
Journal of Molecular Biology, 2007Co-Authors: Ingo P Korndorfer, Florian Brueckner, Arne SkerraAbstract:Abstract The EF-hand proteins S100A8 and S100A9 are important calcium signalling proteins that are involved in wound healing and provide clinically relevant markers of inflammatory processes, such as rheumatoid arthritis and inflammatory bowel disease. Both can form homodimers via distinct modes of association, probably of lesser stability in the case of S100A9, whereas in the presence of calcium S100A8 and S100A9 associate to calprotectin, the physiologically active heterooligomer. Here we describe the crystal structure of the (S100A8/S100A9)2 heterotetramer at 1.8 A resolution. Its quaternary structure illustrates how specific heteroassociation is energetically driven by a more extensive burial of solvent accessible surface areas in both proteins, most pronounced for S100A9, thus leading to a dimer of heterodimers. A major contribution to tetramer association is made by the canonical calcium binding loops in the C-terminal halves of the two proteins. The mode of heterodimerisation in calprotectin more closely resembles the subunit association previously observed in the S100A8 homodimer and provides trans stabilisation for S100A9, which manifests itself in a significantly elongated C-terminal α-helix in the latter. As a consequence, two different putative zinc binding sites emerge at the S100A8/S100A9 subunit interface. One of these corresponds to a high affinity arrangement of three His residues and one Asp side-chain, which is unique to the heterotetramer. This structural feature explains the well known Zn2+ binding activity of calprotectin, whose overexpression can cause strong dysregulation of zinc homeostasis with severe clinical symptoms.
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the crystal structure of the human s100a8 S100A9 2 heterotetramer calprotectin illustrates how conformational changes of interacting alpha helices can determine specific association of two ef hand proteins
Journal of Molecular Biology, 2007Co-Authors: Ingo P Korndorfer, Florian Brueckner, Arne SkerraAbstract:The EF-hand proteins S100A8 and S100A9 are important calcium signalling proteins that are involved in wound healing and provide clinically relevant markers of inflammatory processes, such as rheumatoid arthritis and inflammatory bowel disease. Both can form homodimers via distinct modes of association, probably of lesser stability in the case of S100A9, whereas in the presence of calcium S100A8 and S100A9 associate to calprotectin, the physiologically active heterooligomer. Here we describe the crystal structure of the (S100A8/S100A9)(2) heterotetramer at 1.8 A resolution. Its quaternary structure illustrates how specific heteroassociation is energetically driven by a more extensive burial of solvent accessible surface areas in both proteins, most pronounced for S100A9, thus leading to a dimer of heterodimers. A major contribution to tetramer association is made by the canonical calcium binding loops in the C-terminal halves of the two proteins. The mode of heterodimerisation in calprotectin more closely resembles the subunit association previously observed in the S100A8 homodimer and provides trans stabilisation for S100A9, which manifests itself in a significantly elongated C-terminal alpha-helix in the latter. As a consequence, two different putative zinc binding sites emerge at the S100A8/S100A9 subunit interface. One of these corresponds to a high affinity arrangement of three His residues and one Asp side-chain, which is unique to the heterotetramer. This structural feature explains the well known Zn(2+) binding activity of calprotectin, whose overexpression can cause strong dysregulation of zinc homeostasis with severe clinical symptoms.
Florian Brueckner - One of the best experts on this subject based on the ideXlab platform.
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the crystal structure of the human s100a8 S100A9 2 heterotetramer calprotectin illustrates how conformational changes of interacting α helices can determine specific association of two ef hand proteins
Journal of Molecular Biology, 2007Co-Authors: Ingo P Korndorfer, Florian Brueckner, Arne SkerraAbstract:Abstract The EF-hand proteins S100A8 and S100A9 are important calcium signalling proteins that are involved in wound healing and provide clinically relevant markers of inflammatory processes, such as rheumatoid arthritis and inflammatory bowel disease. Both can form homodimers via distinct modes of association, probably of lesser stability in the case of S100A9, whereas in the presence of calcium S100A8 and S100A9 associate to calprotectin, the physiologically active heterooligomer. Here we describe the crystal structure of the (S100A8/S100A9)2 heterotetramer at 1.8 A resolution. Its quaternary structure illustrates how specific heteroassociation is energetically driven by a more extensive burial of solvent accessible surface areas in both proteins, most pronounced for S100A9, thus leading to a dimer of heterodimers. A major contribution to tetramer association is made by the canonical calcium binding loops in the C-terminal halves of the two proteins. The mode of heterodimerisation in calprotectin more closely resembles the subunit association previously observed in the S100A8 homodimer and provides trans stabilisation for S100A9, which manifests itself in a significantly elongated C-terminal α-helix in the latter. As a consequence, two different putative zinc binding sites emerge at the S100A8/S100A9 subunit interface. One of these corresponds to a high affinity arrangement of three His residues and one Asp side-chain, which is unique to the heterotetramer. This structural feature explains the well known Zn2+ binding activity of calprotectin, whose overexpression can cause strong dysregulation of zinc homeostasis with severe clinical symptoms.
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the crystal structure of the human s100a8 S100A9 2 heterotetramer calprotectin illustrates how conformational changes of interacting alpha helices can determine specific association of two ef hand proteins
Journal of Molecular Biology, 2007Co-Authors: Ingo P Korndorfer, Florian Brueckner, Arne SkerraAbstract:The EF-hand proteins S100A8 and S100A9 are important calcium signalling proteins that are involved in wound healing and provide clinically relevant markers of inflammatory processes, such as rheumatoid arthritis and inflammatory bowel disease. Both can form homodimers via distinct modes of association, probably of lesser stability in the case of S100A9, whereas in the presence of calcium S100A8 and S100A9 associate to calprotectin, the physiologically active heterooligomer. Here we describe the crystal structure of the (S100A8/S100A9)(2) heterotetramer at 1.8 A resolution. Its quaternary structure illustrates how specific heteroassociation is energetically driven by a more extensive burial of solvent accessible surface areas in both proteins, most pronounced for S100A9, thus leading to a dimer of heterodimers. A major contribution to tetramer association is made by the canonical calcium binding loops in the C-terminal halves of the two proteins. The mode of heterodimerisation in calprotectin more closely resembles the subunit association previously observed in the S100A8 homodimer and provides trans stabilisation for S100A9, which manifests itself in a significantly elongated C-terminal alpha-helix in the latter. As a consequence, two different putative zinc binding sites emerge at the S100A8/S100A9 subunit interface. One of these corresponds to a high affinity arrangement of three His residues and one Asp side-chain, which is unique to the heterotetramer. This structural feature explains the well known Zn(2+) binding activity of calprotectin, whose overexpression can cause strong dysregulation of zinc homeostasis with severe clinical symptoms.
