TY - JOUR
T1 - A Targetable N-Terminal Motif Orchestrates α-Synuclein Oligomer-to-Fibril Conversion
AU - Santos, Jaime
AU - Cuellar, Jorge
AU - Pallarès, Irantzu
AU - Byrd, Emily J
AU - Lends, Alons
AU - Moro, Fernando
AU - Abdul-Shukkoor, Muhammed Bilal
AU - Pujols, Jordi
AU - Velasco-Carneros, Lorea
AU - Sobott, Frank
AU - Otzen, Daniel E
AU - Calabrese, Antonio N
AU - Muga, Arturo
AU - Pedersen, Jan Skov
AU - Loquet, Antoine
AU - Valpuesta, Jose María
AU - Radford, Sheena E
AU - Ventura, Salvador
PY - 2024/5
Y1 - 2024/5
N2 - Oligomeric species populated during α-synuclein aggregation are considered key drivers of neurodegeneration in Parkinson's disease. However, the development of oligomer-targeting therapeutics is constrained by our limited knowledge of their structure and the molecular determinants driving their conversion to fibrils. Phenol-soluble modulin α3 (PSMα3) is a nanomolar peptide binder of α-synuclein oligomers that inhibits aggregation by blocking oligomer-to-fibril conversion. Here, we investigate the binding of PSMα3 to α-synuclein oligomers to discover the mechanistic basis of this protective activity. We find that PSMα3 selectively targets an α-synuclein N-terminal motif (residues 36-61) that populates a distinct conformation in the mono- and oligomeric states. This α-synuclein region plays a pivotal role in oligomer-to-fibril conversion as its absence renders the central NAC domain insufficient to prompt this structural transition. The hereditary mutation G51D, associated with early onset Parkinson's disease, causes a conformational fluctuation in this region, leading to delayed oligomer-to-fibril conversion and an accumulation of oligomers that are resistant to remodeling by molecular chaperones. Overall, our findings unveil a new targetable region in α-synuclein oligomers, advance our comprehension of oligomer-to-amyloid fibril conversion, and reveal a new facet of α-synuclein pathogenic mutations.
AB - Oligomeric species populated during α-synuclein aggregation are considered key drivers of neurodegeneration in Parkinson's disease. However, the development of oligomer-targeting therapeutics is constrained by our limited knowledge of their structure and the molecular determinants driving their conversion to fibrils. Phenol-soluble modulin α3 (PSMα3) is a nanomolar peptide binder of α-synuclein oligomers that inhibits aggregation by blocking oligomer-to-fibril conversion. Here, we investigate the binding of PSMα3 to α-synuclein oligomers to discover the mechanistic basis of this protective activity. We find that PSMα3 selectively targets an α-synuclein N-terminal motif (residues 36-61) that populates a distinct conformation in the mono- and oligomeric states. This α-synuclein region plays a pivotal role in oligomer-to-fibril conversion as its absence renders the central NAC domain insufficient to prompt this structural transition. The hereditary mutation G51D, associated with early onset Parkinson's disease, causes a conformational fluctuation in this region, leading to delayed oligomer-to-fibril conversion and an accumulation of oligomers that are resistant to remodeling by molecular chaperones. Overall, our findings unveil a new targetable region in α-synuclein oligomers, advance our comprehension of oligomer-to-amyloid fibril conversion, and reveal a new facet of α-synuclein pathogenic mutations.
KW - alpha-Synuclein/chemistry
KW - Humans
KW - Parkinson Disease/metabolism
KW - Amino Acid Motifs
UR - http://www.scopus.com/inward/record.url?scp=85192058292&partnerID=8YFLogxK
U2 - 10.1021/jacs.4c02262
DO - 10.1021/jacs.4c02262
M3 - Journal article
C2 - 38683963
SN - 0002-7863
VL - 146
SP - 12702
EP - 12711
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 18
ER -