The Stabilization of S100A9 Structure by Calcium Inhibits the Formation of Amyloid Fibrils
The calcium-binding protein S100A9 is recognized as an important component of the brain neuroinflammatory response to the onset and development of neurodegenerative disease. S100A9 is intrinsically amyloidogenic and in vivo co-aggregates with amyloid-β peptide and α-synuclein in Alzheimer’s and Park...
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MDPI AG
2023-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/17/13200 |
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| author | Ella Sanders Rebecca Csondor Darius Šulskis Ieva Baronaitė Vytautas Smirnovas Luckshi Maheswaran Jack Horrocks Rory Munro Christina Georgiadou Istvan Horvath Ludmilla A. Morozova-Roche Philip T. F. Williamson |
| author_facet | Ella Sanders Rebecca Csondor Darius Šulskis Ieva Baronaitė Vytautas Smirnovas Luckshi Maheswaran Jack Horrocks Rory Munro Christina Georgiadou Istvan Horvath Ludmilla A. Morozova-Roche Philip T. F. Williamson |
| author_sort | Ella Sanders |
| collection | DOAJ |
| description | The calcium-binding protein S100A9 is recognized as an important component of the brain neuroinflammatory response to the onset and development of neurodegenerative disease. S100A9 is intrinsically amyloidogenic and in vivo co-aggregates with amyloid-β peptide and α-synuclein in Alzheimer’s and Parkinson’s diseases, respectively. It is widely accepted that calcium dyshomeostasis plays an important role in the onset and development of these diseases, and studies have shown that elevated levels of calcium limit the potential for S100A9 to adopt a fibrillar structure. The exact mechanism by which calcium exerts its influence on the aggregation process remains unclear. Here we demonstrate that despite S100A9 exhibiting α-helical secondary structure in the absence of calcium, the protein exhibits significant plasticity with interconversion between different conformational states occurring on the micro- to milli-second timescale. This plasticity allows the population of conformational states that favour the onset of fibril formation. Magic-angle spinning solid-state NMR studies of the resulting S100A9 fibrils reveal that the S100A9 adopts a single structurally well-defined rigid fibrillar core surrounded by a shell of approximately 15–20 mobile residues, a structure that persists even when fibrils are produced in the presence of calcium ions. These studies highlight how the dysregulation of metal ion concentrations can influence the conformational equilibria of this important neuroinflammatory protein to influence the rate and nature of the amyloid deposits formed. |
| first_indexed | 2024-03-10T23:21:57Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T23:21:57Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-dbe57bb098c44c8eb6ffe807cde740dc2023-11-19T08:13:53ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-08-0124171320010.3390/ijms241713200The Stabilization of S100A9 Structure by Calcium Inhibits the Formation of Amyloid FibrilsElla Sanders0Rebecca Csondor1Darius Šulskis2Ieva Baronaitė3Vytautas Smirnovas4Luckshi Maheswaran5Jack Horrocks6Rory Munro7Christina Georgiadou8Istvan Horvath9Ludmilla A. Morozova-Roche10Philip T. F. Williamson11Centre for Biological Sciences, University of Southampton, Southampton SO17 1BJ, UKCentre for Biological Sciences, University of Southampton, Southampton SO17 1BJ, UKSector of Amyloid Research, Institute of Biotechnology, Life Sciences Centre, Vilnius University, LT-10257 Vilnius, LithuaniaSector of Amyloid Research, Institute of Biotechnology, Life Sciences Centre, Vilnius University, LT-10257 Vilnius, LithuaniaSector of Amyloid Research, Institute of Biotechnology, Life Sciences Centre, Vilnius University, LT-10257 Vilnius, LithuaniaCentre for Biological Sciences, University of Southampton, Southampton SO17 1BJ, UKCentre for Biological Sciences, University of Southampton, Southampton SO17 1BJ, UKCentre for Biological Sciences, University of Southampton, Southampton SO17 1BJ, UKCentre for Biological Sciences, University of Southampton, Southampton SO17 1BJ, UKDepartment of Medical Biochemistry and Biophysics, Umeå University, SE-90187 Umeå, SwedenDepartment of Medical Biochemistry and Biophysics, Umeå University, SE-90187 Umeå, SwedenCentre for Biological Sciences, University of Southampton, Southampton SO17 1BJ, UKThe calcium-binding protein S100A9 is recognized as an important component of the brain neuroinflammatory response to the onset and development of neurodegenerative disease. S100A9 is intrinsically amyloidogenic and in vivo co-aggregates with amyloid-β peptide and α-synuclein in Alzheimer’s and Parkinson’s diseases, respectively. It is widely accepted that calcium dyshomeostasis plays an important role in the onset and development of these diseases, and studies have shown that elevated levels of calcium limit the potential for S100A9 to adopt a fibrillar structure. The exact mechanism by which calcium exerts its influence on the aggregation process remains unclear. Here we demonstrate that despite S100A9 exhibiting α-helical secondary structure in the absence of calcium, the protein exhibits significant plasticity with interconversion between different conformational states occurring on the micro- to milli-second timescale. This plasticity allows the population of conformational states that favour the onset of fibril formation. Magic-angle spinning solid-state NMR studies of the resulting S100A9 fibrils reveal that the S100A9 adopts a single structurally well-defined rigid fibrillar core surrounded by a shell of approximately 15–20 mobile residues, a structure that persists even when fibrils are produced in the presence of calcium ions. These studies highlight how the dysregulation of metal ion concentrations can influence the conformational equilibria of this important neuroinflammatory protein to influence the rate and nature of the amyloid deposits formed.https://www.mdpi.com/1422-0067/24/17/13200amyloidS100A9protein stabilityneurodegenerative diseaseAlzheimer’s diseaseParkinson’s disease |
| spellingShingle | Ella Sanders Rebecca Csondor Darius Šulskis Ieva Baronaitė Vytautas Smirnovas Luckshi Maheswaran Jack Horrocks Rory Munro Christina Georgiadou Istvan Horvath Ludmilla A. Morozova-Roche Philip T. F. Williamson The Stabilization of S100A9 Structure by Calcium Inhibits the Formation of Amyloid Fibrils International Journal of Molecular Sciences amyloid S100A9 protein stability neurodegenerative disease Alzheimer’s disease Parkinson’s disease |
| title | The Stabilization of S100A9 Structure by Calcium Inhibits the Formation of Amyloid Fibrils |
| title_full | The Stabilization of S100A9 Structure by Calcium Inhibits the Formation of Amyloid Fibrils |
| title_fullStr | The Stabilization of S100A9 Structure by Calcium Inhibits the Formation of Amyloid Fibrils |
| title_full_unstemmed | The Stabilization of S100A9 Structure by Calcium Inhibits the Formation of Amyloid Fibrils |
| title_short | The Stabilization of S100A9 Structure by Calcium Inhibits the Formation of Amyloid Fibrils |
| title_sort | stabilization of s100a9 structure by calcium inhibits the formation of amyloid fibrils |
| topic | amyloid S100A9 protein stability neurodegenerative disease Alzheimer’s disease Parkinson’s disease |
| url | https://www.mdpi.com/1422-0067/24/17/13200 |
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