Tyrosine Hydroxylase Binding to Phospholipid Membranes Prompts Its Amyloid Aggregation and Compromises Bilayer Integrity
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Tyrosine hydroxylase (TH), a rate-limiting enzyme in the synthesis of catecholamine neurotransmitters and hormones, binds to negatively charged phospholipid membranes. Binding to both large and giant unilamellar vesicles causes membrane permeabilization, as observed by efflux and influx of fluorescence dyes. Whereas the initial protein-membrane interaction involves the N-terminal tail that constitutes an extension of the regulatory ACT-domain, prolonged membrane binding induces misfolding and self-oligomerization of TH over time as shown by circular dichroism and Thioflavin T fluorescence. The gradual amyloid-like aggregation likely occurs through cross-β interactions involving aggregation-prone motives in the catalytic domains, consistent with the formation of chain and ring-like protofilaments observed by atomic force microscopy in monolayer-bound TH. PC12 cells treated with the neurotoxin 6-hydroxydopamine displayed increased TH levels in the mitochondrial fraction, while incubation of isolated mitochondria with TH led to a decrease in the mitochondrial membrane potential. Furthermore, cell-substrate impedance and viability assays showed that supplementing the culture media with TH compromises cell viability over time. Our results revealed that the disruptive effect of TH on cell membranes may be a cytotoxic and pathogenic factor if the regulation and intracellular stability of TH is compromised.
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TH protein, particularly phosphorylated TH, forms intracellular aggregates easily.
“TH protein, particularly phosphorylated TH, apparently forms intracellular aggregates easily [70,72].”
From Degradation of Tyrosine Hydroxylase by the Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease and Dopa-Responsive Dystonia (2020) · cites this paper as [72]
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Kawahata, I., & Fukunaga, K. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21113779 · Cited by 71 · see citing works
- Authors
- Baumann, A., Jorge-Finnigan, A., Jung-KC, K., Sauter, A., Horvath, I., Morozova-Roche, L. A., & Martinez, A.
- Affiliations
- Haukeland University Hospital (NO)
- University of Bergen (NO)
- Corresponding author
- Baumann, Anne
- Venue
- Scientific Reports
- Published
- 2016-12-22
- Volume
- 6
- Issue
- 1
- Pages
- 39488-39488
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5177901
- OpenAlex
- W2567492961
- Cited by
- 20
- References
- 66
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 1 · 2022: 1 · 2021: 3 · 2020: 3 · 2019: 3 · 2018: 2 · 2017: 1
- FWCI
- 1.04
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DiVA at Umeå University (Umeå University) (submittedVersion, other-oa)
- Funders
- Stiftelsen Kristian Gerhard Jebsen
- Federation of European Biochemical Societies
- Universitetet i Bergen
- Norges Forskningsråd (299972)
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Keywords
- tyrosine hydroxylase, protein-membrane binding, phospholipid membranes, amyloid fibril formation, self-oligomerization, membrane permeabilization, N-terminal tail, ACT domain, 6-hydroxydopamine, mitochondrial membrane potential, cytotoxicity, catecholamine synthesis, protein misfolding
- MeSH terms
- Amyloid, Animals, Cell Membrane, Cell Survival, Circular Dichroism, Flow Cytometry, Humans, Lipid Bilayers, Liposomes, Mitochondria, Molecular Conformation, Permeability, Phosphatidylcholines, Phospholipids, Subcellular Fractions, Thiazoles, Tyrosine 3-Monooxygenase, Gene Expression Regulation, Neoplastic, PC12 Cells, Microscopy, Confocal, Microscopy, Atomic Force, Catalytic Domain, Rats, Benzothiazoles, HEK293 Cells
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