The N-terminal repeat domain of alpha-synuclein inhibits beta-sheet and amyloid fibril formation.
The conversion of alpha-synuclein into amyloid fibrils in the substantia nigra is linked to Parkinson's disease. Alpha-synuclein is natively unfolded in solution, but can be induced to form either alpha-helical or beta-sheet structure depending on its concentration and the solution conditions. The N-terminus of alpha-synuclein comprises seven 11-amino acid repeats (XKTKEGVXXXX) which can form an amphipathic alpha-helix. Why seven repeats, rather than six or eight, survived the evolutionary process is not clear. To probe this question, two sequence variants of alpha-synuclein, one with two fewer (del2) and one with two additional (plus2) repeats, were studied. As compared to wild-type alpha-synuclein, the plus2 variant disfavors the formation of beta-sheet-rich oligomers, including amyloid fibrils. In contrast, the truncated variant, del2, favors beta-sheet and fibril formation. We propose that the repeat number in WT alpha-synuclein represents an evolutionary balance between the functional conformer of alpha-synuclein (alpha-helix and/or random coil) and its pathogenic beta-sheet conformation. N-terminal truncation of alpha-synuclein may promote pathogenesis.
Kessler
Jeffrey C
JC
Center for Neurologic Diseases, Brigham and Women's Hospital, and Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, Massachusetts 02139, USA.
Rochet
Jean-Christophe
JC
Lansbury
Peter T
PT
D000595:Amino Acid Sequence; D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D002942:Circular Dichroism; D003001:Cloning, Molecular; D006801:Humans; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000502:physiology* / Q000648:ultrastructure; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000502:physiology* / Q000648:ultrastructure; D020005:Propanols / Q000737:chemistry; D017510:Protein Folding; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000302:isolation & purification / Q000648:ultrastructure; D017433:Protein Structure, Secondary / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D020449:Repetitive Sequences, Amino Acid / Q000235:genetics / Q000502:physiology*; D051843:Synucleins; D051844:alpha-Synuclein; D006845:Hydrocarbons, Fluorinated
D000682:Amyloid; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D020005:Propanols; D020033:Protein Isoforms; D051843:Synucleins; D051844:alpha-Synuclein; C497604:SNCA protein, human; C001337:hexafluoroisopropanol; D006845:Hydrocarbons, Fluorinated