Dataset Information

Mutant protein A30P ?-synuclein adopts wild-type fibril structure, despite slower fibrillation kinetics.

ABSTRACT: ?-Synuclein (AS) is associated with both sporadic and familial forms of Parkinson disease (PD). In sporadic disease, wild-type AS fibrillates and accumulates as Lewy bodies within dopaminergic neurons of the substantia nigra. The accumulation of misfolded AS is associated with the death of these neurons, which underlies many of the clinical features of PD. In addition, a rare missense mutation in AS, A30P, is associated with highly penetrant, autosomal dominant PD, although the pathogenic mechanism is unclear. A30P AS fibrillates more slowly than the wild-type (WT) protein in vitro and has been reported to preferentially adopt a soluble, protofibrillar conformation. This has led to speculation that A30P forms aggregates that are distinct in structure compared with wild-type AS. Here, we perform a detailed comparison of the chemical shifts and secondary structures of these fibrillar species, based upon our recent characterization of full-length WT fibrils. We have assigned A30P AS fibril chemical shifts de novo and used them to determine its secondary structure empirically. Our results illustrate that although A30P forms fibrils more slowly than WT in vitro, the chemical shifts and secondary structure of the resultant fibrils are in high agreement, demonstrating a conserved ?-sheet core.

SUBMITTER: Lemkau LR

PROVIDER: S-EPMC3322835 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mutant protein A30P α-synuclein adopts wild-type fibril structure, despite slower fibrillation kinetics.

Lemkau Luisel R LR Comellas Gemma G Kloepper Kathryn D KD Woods Wendy S WS George Julia M JM Rienstra Chad M CM

The Journal of biological chemistry 20120209 14

α-Synuclein (AS) is associated with both sporadic and familial forms of Parkinson disease (PD). In sporadic disease, wild-type AS fibrillates and accumulates as Lewy bodies within dopaminergic neurons of the substantia nigra. The accumulation of misfolded AS is associated with the death of these neurons, which underlies many of the clinical features of PD. In addition, a rare missense mutation in AS, A30P, is associated with highly penetrant, autosomal dominant PD, although the pathogenic mechan ...[more]

PMID: 22334684

Similar Datasets

Project description:The genetic missense A30P mutation of the wild-type ?-synuclein protein results in the replacement of the 30th amino acid residue from alanine (Ala) to proline (Pro) and was initially found in the members of a German family who developed Parkinson's disease. Even though the structures of these proteins have been measured before, detailed understanding about the structures and their relationships with free energy landscapes is lacking, which is of interest to provide insights into the pathogenic mechanism of Parkinson's disease. We report the secondary and tertiary structures and conformational free energy landscapes of the wild-type and A30P mutant-type ?-synuclein proteins in an aqueous solution environment via extensive parallel tempering molecular dynamics simulations along with thermodynamic calculations. In addition, we present the residual secondary structure component transition stabilities at the atomic level with dynamics in terms of free energy change calculations using a new strategy that we reported most recently. Our studies yield new interesting results; for instance, we find that the A30P mutation has local as well as long-range effects on the structural properties of the wild-type ?-synuclein protein. The helical content at Ala18-Gly31 is less prominent in comparison to the wild-type ?-synuclein protein. The ?-sheet structure abundance decreases in the N-terminal region upon A30P mutation of the wild-type ?-synuclein, whereas the NAC and C-terminal regions possess larger tendencies for ?-sheet structure formation. Long-range intramolecular protein interactions are less abundant upon A30P mutation, especially between the NAC and C-terminal regions, which is linked to the less compact and less stable structures of the A30P mutant-type rather than the wild-type ?-synuclein protein. Results including the usage of our new strategy for secondary structure transition stabilities show that the A30P mutant-type ?-synuclein tendency toward aggregation is higher than the wild-type ?-synuclein but we also find that the C-terminal and NAC regions of the A30P mutant-type ?-synuclein are reactive toward fibrillzation and aggregation based on atomic level studies with dynamics in an aqueous solution environment. Therefore, we propose that small molecules or drugs blocking the specific residues, which we report herein, located in the NAC- and C-terminal regions of the A30P mutant-type ?-synuclein protein might help to reduce the toxicity of the A30P mutant-type ?-synuclein protein.

Dataset Information

Mutant protein A30P ?-synuclein adopts wild-type fibril structure, despite slower fibrillation kinetics.

Publications

Mutant protein A30P α-synuclein adopts wild-type fibril structure, despite slower fibrillation kinetics.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets