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Structural flexibility and heterogeneity of recombinant human glial fibrillary acidic protein (GFAP)
Open accessPublished version of a preprint
Abstract
Glial fibrillary acidic protein (GFAP) is a promising biomarker for brain and spinal cord disorders. Recent studies have highlighted the differences in the reliability of GFAP measurements in different biological matrices. The reason for these discrepancies is poorly understood as our knowledge of the protein's 3‐dimensional conformation, proteoforms, and aggregation remains limited. Here, we investigate the structural properties of GFAP under different conditions. For this, we characterized recombinant GFAP proteins from various suppliers and applied hydrogen‐deuterium exchange mass spectrometry (HDX‐MS) to provide a snapshot of the conformational dynamics of GFAP in artificial cerebrospinal fluid (aCSF) compared to the phosphate buffer. Our findings indicate that recombinant GFAP exists in various conformational species. Furthermore, we show that GFAP dimers remained intact under denaturing conditions. HDX‐MS experiments show an overall decrease in H‐bonding and an increase in solvent accessibility of GFAP in aCSF compared to the phosphate buffer, with clear indications of mixed EX2 and EX1 kinetics. To understand possible structural interface regions and the evolutionary conservation profiles, we combined HDX‐MS results with the predicted GFAP‐dimer structure by AlphaFold‐Multimer. We found that deprotected regions with high structural flexibility in aCSF overlap with predicted conserved dimeric 1B and 2B domain interfaces. Structural property predictions combined with the HDX data show an overall deprotection and signatures of aggregation in aCSF. We anticipate that the outcomes of this research will contribute to a deeper understanding of the structural flexibility of GFAP and ultimately shed light on its behavior in different biological matrices.
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Highly accurate protein structure prediction with AlphaFold
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Metadata
- Authors
- Gogishvili, D., Illes‐Toth, E., Harris, M. J., Hopley, C., Teunissen, C. E., & Abeln, S.
- Affiliations
- Utrecht University (NL)
- LGC (GB)
- Amsterdam Neuroscience (NL)
- Corresponding author
- Gogishvili, Dea
- Venue
- Proteins: Structure, Function, and Bioinformatics
- Publisher
- Wiley
- Published
- 2023-12-27
- Volume
- 92
- Issue
- 5
- Pages
- 649-664
- ISSN
- 0887-3585 (ISSN-L)
- 1097-0134
- OpenAlex
- W4390269103
- Cited by
- 8
- References
- 7
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 1
- FWCI
- 0.73
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proteins Structure Function and Bioinformatics (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- VU Research Portal (publishedVersion, other-oa)
- Pure Amsterdam UMC (acceptedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion, other-oa)
- Funders
- ZonMw
- Selfridges Group Foundation
- Alzheimer's Drug Discovery Foundation
- Alzheimer's Association
- Alzheimer Nederland
- European Commission
- Topics
- Physical Sciences › Chemistry › Spectroscopy › Mass Spectrometry Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
- Keywords
- glial fibrillary acidic protein, protein conformational dynamics, structural heterogeneity, recombinant protein, hydrogen-deuterium exchange, artificial cerebrospinal fluid, protein aggregation, solvent accessibility, hydrogen bonding, dimer interface
- MeSH terms
- Glial Fibrillary Acidic Protein, Humans, Phosphates, Protein Conformation, Recombinant Proteins, Reproducibility of Results, Deuterium Exchange Measurement
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