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Calcium-triggered membrane interaction of the alpha-synuclein acidic tail
Shiori Tamamizu-Kato1, Malathi G Kosaraju, Hiroyuki Kato
1Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, California 94609, USA.
Biochemistry
|September 7, 2006
Summary
Calcium ions (Ca2+) trigger the acidic tail of alpha-synuclein to interact with lipids, potentially driving protein aggregation in Parkinson's disease (PD). This calcium-induced membrane association is a key step in alpha-synuclein aggregation, relevant to PD pathogenesis.
Area of Science:
- Biochemistry
- Neuroscience
- Molecular Biology
Background:
- Alpha-synuclein (alpha-syn) aggregation into Lewy bodies is central to Parkinson's disease (PD) pathogenesis.
- Alpha-synuclein comprises a lipid-binding N-terminal domain and an acidic C-terminal tail.
- The role of calcium ions (Ca2+) in modulating alpha-synuclein's interaction with lipids and its conformational changes remains incompletely understood.
Purpose of the Study:
- To investigate the effect of Ca2+ on the conformation of the acidic tail of lipid-bound alpha-synuclein.
- To elucidate the mechanism of alpha-synuclein's membrane association and its potential role in aggregation.
Main Methods:
- Utilized pyrene fluorescence spectroscopy to monitor the microenvironment polarity of alpha-synuclein's N-terminal and acidic tail domains.
- Employed recombinant human alpha-synuclein labeled with pyrene at specific domains.
- Assessed changes in fluorescence emission intensity and susceptibility to quenching in response to lipid binding and Ca2+ addition.
Main Results:
- Lipid binding primarily involved the N-terminal domain of alpha-synuclein, anchoring it to the lipid surface.
- Ca2+ addition induced a conformational change in the acidic tail, promoting its interaction with the lipid membrane.
- Ca2+ also increased the beta-sheet content of membrane-associated alpha-synuclein, suggesting enhanced aggregation propensity.
Conclusions:
- A model is proposed where N-terminal lipid binding is followed by Ca2+-triggered acidic tail membrane association, facilitating alpha-synuclein aggregation.
- These findings highlight the critical role of Ca2+ dysregulation, potentially linked to oxidative stress, in alpha-synuclein aggregation in PD.
- The study provides insights into the molecular mechanisms underlying PD pathogenesis and potential therapeutic targets.
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