Structure based aggregation studies reveal the presence of helix-rich intermediate during alpha-Synuclein aggregation
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Title |
Structure based aggregation studies reveal the presence of helix-rich intermediate during alpha-Synuclein aggregation
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Creator |
GHOSH, D
SINGH, PK SAHAY, S JHA, NN JACOB, RS SEN, S KUMAR, A RIEK, R MAJI, SK |
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Subject |
ISLET AMYLOID POLYPEPTIDE
BETA-PROTEIN FIBRILLOGENESIS FAMILIAL PARKINSONS-DISEASE CIRCULAR-DICHROISM SPECTRA A-BETA MEMBRANE DISRUPTION IN-VITRO SECONDARY STRUCTURE NMR-SPECTROSCOPY FIBRIL FORMATION |
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Description |
Mechanistic understanding of nucleation dependent polymerization by a-synuclein (alpha-Syn) into toxic oligomers and amyloids is important for the drug development against Parkinson's disease. However the structural and morphological characterization during nucleation and subsequent fibrillation process of alpha-Syn is not clearly understood. Using a variety of complementary biophysical techniques monitoring entire pathway of nine different synucleins, we found that transition of unstructured conformation into beta-sheet rich fibril formation involves helix-rich intermediates. These intermediates are common for all aggregating synucleins, contain high solvent-exposed hydrophobic surfaces, are cytotoxic to SHSY-5Y cells and accelerate alpha-Syn aggregation efficiently. A multidimensional NMR study characterizing the intermediate accompanied with site-specific fluorescence study suggests that the N-terminal and central portions mainly participate in the helix-rich intermediate formation while the C-terminus remained in an extended conformation. However, significant conformational transitions occur at the middle and at the C-terminus during helix to beta-sheet transition as evident from Trp fluorescence study. Since partial helix-rich intermediates were also observed for other amyloidogenic proteins such as Ab and IAPP, we hypothesize that this class of intermediates may be one of the important intermediates for amyloid formation pathway by many natively unstructured protein/peptides and represent a potential target for drug development against amyloid diseases.
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Publisher |
NATURE PUBLISHING GROUP
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Date |
2016-01-15T06:37:49Z
2016-01-15T06:37:49Z 2015 |
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Type |
Article
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Identifier |
SCIENTIFIC REPORTS, 5
2045-2322 http://dx.doi.org/10.1038/srep09228 http://dspace.library.iitb.ac.in/jspui/handle/100/17951 |
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Language |
en
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