Alternative Structures of α-Synuclein
The object of our analysis is the structure of alpha-synuclein (ASyn), which, under in vivo conditions, associates with presynaptic vesicles. Misfolding of ASyn is known to be implicated in Parkinson’s disease. The availability of structural information for both the micelle-bound and amylo...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-01-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/25/3/600 |
| _version_ | 1818265523153010688 |
|---|---|
| author | Dawid Dułak Małgorzata Gadzała Mateusz Banach Leszek Konieczny Irena Roterman |
| author_facet | Dawid Dułak Małgorzata Gadzała Mateusz Banach Leszek Konieczny Irena Roterman |
| author_sort | Dawid Dułak |
| collection | DOAJ |
| description | The object of our analysis is the structure of alpha-synuclein (ASyn), which, under in vivo conditions, associates with presynaptic vesicles. Misfolding of ASyn is known to be implicated in Parkinson’s disease. The availability of structural information for both the micelle-bound and amyloid form of ASyn enables us to speculate on the specific mechanism of amyloid transformation. This analysis is all the more interesting given the fact that—Unlike in Aβ(1−42) amyloids—only the central fragment (30−100) of ASyn has a fibrillar structure, whereas, its N- and C-terminal fragments (1−30 and 100−140, respectively) are described as random coils. Our work addresses the following question: Can the ASyn chain—as well as the aforementioned individual fragments—adopt globular conformations? In order to provide an answer, we subjected the corresponding sequences to simulations carried out using Robetta and I-Tasser, both of which are regarded as accurate protein structure predictors. In addition, we also applied the fuzzy oil drop (FOD) model, which, in addition to optimizing the protein’s internal free energy, acknowledges the presence of an external force field contributed by the aqueous solvent. This field directs hydrophobic residues to congregate near the center of the protein body while exposing hydrophilic residues on its surface. Comparative analysis of the obtained models suggests that fragments which do not participate in forming the amyloid fibril (i.e., 1−30 and 100−140) can indeed attain globular conformations. We also explain the influence of mutations observed in vivo upon the susceptibility of ASyn to undergo amyloid transformation. In particular, the 30−100 fragment (which adopts a fibrillar structure in PDB) is not predicted to produce a centralized hydrophobic core by any of the applied toolkits (Robetta, I-Tasser, and FOD). This means that in order to minimize the entropically disadvantageous contact between hydrophobic residues and the polar solvent, ASyn adopts the form of a ribbonlike micelle (rather than a spherical one). In other words, the ribbonlike micelle represents a synergy between the conformational preferences of the protein chain and the influence of its environment. |
| first_indexed | 2024-12-12T19:52:09Z |
| format | Article |
| id | doaj.art-22986ad5fc8548059a0d33d82fa6dd91 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-12T19:52:09Z |
| publishDate | 2020-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-22986ad5fc8548059a0d33d82fa6dd912022-12-22T00:13:57ZengMDPI AGMolecules1420-30492020-01-0125360010.3390/molecules25030600molecules25030600Alternative Structures of α-SynucleinDawid Dułak0Małgorzata Gadzała1Mateusz Banach2Leszek Konieczny3Irena Roterman4Faculty of Physics, Astronomy and Applied Computer Science, Jagiellonian University, Łojasiewicza 11, 30-348 Kraków, PolandACK–Cyfronet AGH, Nawojki 11, 30-950 Krakow, PolandDepartment of Bioinformatics and Telemedicine, Jagiellonian University—Medical College, Łazarza 16, 31-530 Krakow, PolandChair of Medical Biochemistry, Jagiellonian University–Medical College, Kopernika 7, 31-034 Kraków, PolandDepartment of Bioinformatics and Telemedicine, Jagiellonian University—Medical College, Łazarza 16, 31-530 Krakow, PolandThe object of our analysis is the structure of alpha-synuclein (ASyn), which, under in vivo conditions, associates with presynaptic vesicles. Misfolding of ASyn is known to be implicated in Parkinson’s disease. The availability of structural information for both the micelle-bound and amyloid form of ASyn enables us to speculate on the specific mechanism of amyloid transformation. This analysis is all the more interesting given the fact that—Unlike in Aβ(1−42) amyloids—only the central fragment (30−100) of ASyn has a fibrillar structure, whereas, its N- and C-terminal fragments (1−30 and 100−140, respectively) are described as random coils. Our work addresses the following question: Can the ASyn chain—as well as the aforementioned individual fragments—adopt globular conformations? In order to provide an answer, we subjected the corresponding sequences to simulations carried out using Robetta and I-Tasser, both of which are regarded as accurate protein structure predictors. In addition, we also applied the fuzzy oil drop (FOD) model, which, in addition to optimizing the protein’s internal free energy, acknowledges the presence of an external force field contributed by the aqueous solvent. This field directs hydrophobic residues to congregate near the center of the protein body while exposing hydrophilic residues on its surface. Comparative analysis of the obtained models suggests that fragments which do not participate in forming the amyloid fibril (i.e., 1−30 and 100−140) can indeed attain globular conformations. We also explain the influence of mutations observed in vivo upon the susceptibility of ASyn to undergo amyloid transformation. In particular, the 30−100 fragment (which adopts a fibrillar structure in PDB) is not predicted to produce a centralized hydrophobic core by any of the applied toolkits (Robetta, I-Tasser, and FOD). This means that in order to minimize the entropically disadvantageous contact between hydrophobic residues and the polar solvent, ASyn adopts the form of a ribbonlike micelle (rather than a spherical one). In other words, the ribbonlike micelle represents a synergy between the conformational preferences of the protein chain and the influence of its environment.https://www.mdpi.com/1420-3049/25/3/600misfoldinga-synucleinamyloidfibrilprotein foldinghydrophobicity |
| spellingShingle | Dawid Dułak Małgorzata Gadzała Mateusz Banach Leszek Konieczny Irena Roterman Alternative Structures of α-Synuclein Molecules misfolding a-synuclein amyloid fibril protein folding hydrophobicity |
| title | Alternative Structures of α-Synuclein |
| title_full | Alternative Structures of α-Synuclein |
| title_fullStr | Alternative Structures of α-Synuclein |
| title_full_unstemmed | Alternative Structures of α-Synuclein |
| title_short | Alternative Structures of α-Synuclein |
| title_sort | alternative structures of α synuclein |
| topic | misfolding a-synuclein amyloid fibril protein folding hydrophobicity |
| url | https://www.mdpi.com/1420-3049/25/3/600 |
| work_keys_str_mv | AT dawiddułak alternativestructuresofasynuclein AT małgorzatagadzała alternativestructuresofasynuclein AT mateuszbanach alternativestructuresofasynuclein AT leszekkonieczny alternativestructuresofasynuclein AT irenaroterman alternativestructuresofasynuclein |