TY - JOUR
T1 - Three Long-Range Distance Constraints and an Approach Towards a Model for the α-Synuclein-Fibril Fold
AU - Hashemi Shabestari, Maryam
AU - Kumar, Pravin
AU - Segers-Nolten, Ine M.J.
AU - Claessens, Mireille M.A.E.
AU - van Rooijen, Bart D.
AU - Subramaniam, Vinod
AU - Huber, Martina
PY - 2015
Y1 - 2015
N2 - Amyloid fibrils and plaques are the hallmark of neurodegenerative diseases. In Parkinson’s disease, plaques (Lewy bodies) consist predominantly of the α-synuclein (αS) protein. To understand aggregation, the molecular architecture of αS fibrils needs to be known. Here, we determine nm-distance constraints for the protein in the fibril by double electron–electron paramagnetic resonance (DEER) on doubly spin-labeled αS variants, diamagnetically diluted with wild-type αS to suppress intermolecular interactions. Intramolecular distances in three pairs (56/69, 56/90 and 69/90) are reported. An approach to derive a model for the fibril fold from sparse distance data assuming only parallel β-sheets is described. Using the distances obtained in this study as input, a model is obtained with three strands, comprising residues 56–90, in which the strands consist of 8–12 residues each. Limitations of the approach are discussed in detail, showing that the interpretation of the data does not yet yield an unambiguous structure model. Possible avenues to improve this situation are described.
AB - Amyloid fibrils and plaques are the hallmark of neurodegenerative diseases. In Parkinson’s disease, plaques (Lewy bodies) consist predominantly of the α-synuclein (αS) protein. To understand aggregation, the molecular architecture of αS fibrils needs to be known. Here, we determine nm-distance constraints for the protein in the fibril by double electron–electron paramagnetic resonance (DEER) on doubly spin-labeled αS variants, diamagnetically diluted with wild-type αS to suppress intermolecular interactions. Intramolecular distances in three pairs (56/69, 56/90 and 69/90) are reported. An approach to derive a model for the fibril fold from sparse distance data assuming only parallel β-sheets is described. Using the distances obtained in this study as input, a model is obtained with three strands, comprising residues 56–90, in which the strands consist of 8–12 residues each. Limitations of the approach are discussed in detail, showing that the interpretation of the data does not yet yield an unambiguous structure model. Possible avenues to improve this situation are described.
KW - 2023 OA procedure
UR - http://www.scopus.com/inward/record.url?scp=84925460877&partnerID=8YFLogxK
U2 - 10.1007/s00723-014-0622-7
DO - 10.1007/s00723-014-0622-7
M3 - Article
AN - SCOPUS:84925460877
SN - 0937-9347
VL - 46
SP - 369
EP - 388
JO - Applied Magnetic Resonance
JF - Applied Magnetic Resonance
IS - 4
ER -