Tyrosine Hydroxylase Binding to Phospholipid Membranes Prompts Its Amyloid Aggregation and Compromises Bilayer Integrity

Baumann, Anne (author)

Jorge-Finnigan, Ana (author)

Jung-KC, Kunwar (author)

Sauter, Alexander (author)

Horvath, Istvan (author)

Morozova-Roche, Ludmilla A. (author): Umeå universitet,Institutionen för medicinsk kemi och biofysik

Martinez, Aurora (author)

(creator_code:org_t)

2016-12-22
2016
English.
In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6

Related links:: https://doi.org/10.1...; show more...; https://umu.diva-por... (primary) (Raw object); https://www.nature.c...; https://urn.kb.se/re...; https://doi.org/10.1...; show less...

Abstract Subject headings

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-beta 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.

By the author/editor: Baumann, Anne; Jorge-Finnigan, ...; Jung-KC, Kunwar; Sauter, Alexande ...; Horvath, Istvan; Morozova-Roche, ...; show more...; Martinez, Aurora; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Cell and Molecul ...

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