A Structural and Functional Role for 11-mer Repeats in α-Synuclein and Other Exchangeable Lipid Binding Proteins

Bussell, Robert H.; Eliezer, David

doi:10.1016/s0022-2836(03)00520-5

Cited by 415 publications

(550 citation statements)

References 57 publications

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“…These repeats are similar to those found in apolipoproteins, and it was proposed that the lipid interaction of ␣-synuclein could be similar to that of the apolipoproteins (8,13). The involvement of the N terminus in membrane interaction was subsequently confirmed experimentally by analysis of ␣-synuclein deletion mutants (15) and NMR studies of liposomebound ␣-synuclein (18)(19)(20). The latter studies revealed an ordering of the N-terminal repeat regions induced upon membrane binding whereas the highly charged C terminus remained unstructured and, therefore, was not involved in membrane interaction.…”

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confidence: 54%

“…Based on modeling, such extended helical structures were not consistent with a regular helical periodicity of 3.6 aa per turn (20). However, the data could be reconciled by postulating a slight alteration in the periodicity to 3.67 aa per turn, resulting in an ␣-11͞3 helix (11 aa making up 3 turns) (20).The goals of the present study were to obtain structural information for vesicle-bound ␣-synuclein, and to determine whether the models proposed for SDS-bound ␣-synuclein could be applicable to the membrane-bound form. Toward this end, we used site-directed spin labeling (SDSL) combined with EPR spectroscopy (21,22).…”

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confidence: 99%

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Structure of membrane-bound α-synuclein studied by site-directed spin labeling

Jao

Der-Sarkissian²,

Chen³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

345

398

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Many of the proposed physiological functions of ␣-synuclein, a protein involved in the pathogenesis of Parkinson's disease, are related to its ability to interact with phospholipids. To better understand the conformational changes that occur upon membrane binding of monomeric ␣-synuclein, we performed EPR analysis of 47 singly labeled ␣-synuclein derivatives. We show that membrane interaction is mediated by major conformational changes within seven N-terminal 11-aa repeats, which reorganize from a highly dynamic structure into an elongated helical structure devoid of significant tertiary packing. Furthermore, we find that analogous positions from different repeats are in equivalent locations with respect to membrane proximity. These and other findings suggest a curved membrane-dependent ␣-helical structure, wherein each 11-aa repeat takes up three helical turns. Similar helical structures could also apply to apolipoproteins and other lipid-interacting proteins with related 11-aa repeats.T he protein ␣-synuclein is the main component of Lewy bodies, a class of intracellular inclusions that is highly characteristic in Parkinson's disease (PD) (1). A causative role of ␣-synuclein in PD has been supported by genetic studies of familial forms of this disease (2-4) as well as by various animal models (5). In addition to its involvement in PD, ␣-synuclein may also play important roles in Alzheimer's disease, dementia with Lewy bodies, multiple system atrophy, and Hallervorden-Spatz syndrome (6, 7).Although not yet fully understood, the physiological function of ␣-synuclein is likely to involve a role in modulating synaptic plasticity (8), presynaptic vesicle pool size, and neurotransmitter release (9-11), as well as vesicle recycling (12). In agreement with these membrane-related functions, ␣-synuclein has been shown to interact with liposomes in vitro (13-16). According to circular dichroism analysis, this interaction causes ␣-synuclein to undergo a conformational change from an unstructured monomer in solution (13,17,18) to an ␣-helical, membrane-bound protein. Based upon sequence analysis, it was recognized early on that the N-terminal portion of ␣-synuclein was likely to mediate lipid interaction (8,13). The N terminus of ␣-synuclein contains seven repeats, each of which is made up of 11 aa (Fig. 1). These repeats are similar to those found in apolipoproteins, and it was proposed that the lipid interaction of ␣-synuclein could be similar to that of the apolipoproteins (8, 13). The involvement of the N terminus in membrane interaction was subsequently confirmed experimentally by analysis of ␣-synuclein deletion mutants (15) and NMR studies of liposomebound ␣-synuclein (18-20). The latter studies revealed an ordering of the N-terminal repeat regions induced upon membrane binding whereas the highly charged C terminus remained unstructured and, therefore, was not involved in membrane interaction. Beyond these data, however, direct structural information, such as the precise location, length, orientation, and number of...

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confidence: 54%

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confidence: 95%

See 1 more Smart Citation

Structure of membrane-bound α-synuclein studied by site-directed spin labeling

Jao

Der-Sarkissian²,

Chen³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

345

398

View full text Add to dashboard Cite

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“…1) is a 140 amino-acid, intrinsically-disordered protein associated with Parkinson's disease and other neurodegenerative disorders [1][2][3][4][5][6][7][8] whose function is hypothesized to involve its interaction with membranes. [8][9][10][11][12] The protein binds lipids and anionic detergents through the seven imperfect, cationic, 11-amino acid repeats located in its N-terminal and hydrophobic regions.…”

mentioning

confidence: 99%

“…[8][9][10][11][12] The protein binds lipids and anionic detergents through the seven imperfect, cationic, 11-amino acid repeats located in its N-terminal and hydrophobic regions. [6][7][8][13][14][15][16][17][18][19][20] Electron paramagnetic resonance (EPR) data on its complex with small unilamellar vesicles (SUVs) suggest that the first $100 residues of the monomeric protein adopt an a-helical conformation that lies on the membrane surface. [21][22][23][24][25] The last $40 residues lack defined structure and do not appear to be involved in membrane interactions.…”

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¹⁹F NMR studies of α‐synuclein‐membrane interactions

Wang

Pielak

2010

Protein Science

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a-Synuclein function is thought to be related to its membrane binding ability. Solution NMR studies have identified several a-synuclein-membrane interaction modes in small unilamellar vesicles (SUVs), but how membrane properties affect binding remains unclear. Here, we use 19 F NMR to study a-synuclein-membrane interactions by using 3-fluoro-L-tyrosine (3FY) and trifluoromethyl-Lphenylalanine (tfmF) labeled proteins. Our results indicate that the affinity is affected by both the head group and the acyl chain of the SUV. Negatively charged head groups have higher affinity, but different head groups with the same charge also affect binding. We show that the saturation of the acyl chain has a dramatic effect on the a-synuclein-membrane interactions by studying lipids with the same head group but different chains. Taken together, the data show that a-synuclein's N-terminal region is the most important determinate of SUV binding, but its C-terminal region also modulates the interactions. Our data support the existence of multiple tight phospholipid-binding modes, a result incompatible with the model that a-synuclein lies solely on the membrane surface.

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High‐density lipoprotein‐like particle formation of Synuclein variants

Kumari

Riek

2017

FEBS Letters

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α-Synuclein (α-Syn) is an intrinsically disordered protein in solution whose fibrillar aggregates are the hallmark of Parkinson's disease (PD). Although the specific function of α-Syn is still unclear, its high structural plasticity is key for the interactions of α-Syn with biological membranes. Recently, it has been observed that α-Syn is able to form high-density lipoprotein-like (HDL-like) particles that are reminiscent of self-assembling phospholipid bilayer nanodiscs. Here, we extended our preparation method for the production of α-Syn lipoprotein particles to the β- and γ-Syn variants, and the PD-related familial α-Syn mutants. We show that all human Syns can form stable and homogeneous populations of HDL-like particles with distinct morphologies. Our results characterize the impact of the individual Syns on the formation capacity of these particles and indicate that Syn HDL-like particles are neither causing toxicity nor a toxicity-related loss of α-Syn in PD.

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A Structural and Functional Role for 11-mer Repeats in α-Synuclein and Other Exchangeable Lipid Binding Proteins

Cited by 415 publications

References 57 publications

Structure of membrane-bound α-synuclein studied by site-directed spin labeling

Structure of membrane-bound α-synuclein studied by site-directed spin labeling

¹⁹F NMR studies of α‐synuclein‐membrane interactions

High‐density lipoprotein‐like particle formation of Synuclein variants

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A Structural and Functional Role for 11-mer Repeats in α-Synuclein and Other Exchangeable Lipid Binding Proteins

Cited by 415 publications

References 57 publications

Structure of membrane-bound α-synuclein studied by site-directed spin labeling

Structure of membrane-bound α-synuclein studied by site-directed spin labeling

19F NMR studies of α‐synuclein‐membrane interactions

High‐density lipoprotein‐like particle formation of Synuclein variants

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¹⁹F NMR studies of α‐synuclein‐membrane interactions