| Summary: | Abnormally misfolded and aggregated α-synuclein (αsyn) is the hallmark of Parkinson's disease (PD). Molecular chaperone protein disulfide isomerase (PDI) has been shown to interact with αsyn and inhibit its aggregation in vitro, but the mechanism for the recognition of αsyn by PDI is not yet clear. Herein, we used nuclear magnetic resonance (NMR) spectroscopy to identify that human PDI b'xa' bound with the N-terminal domain of αsyn, and thioflavin T (ThT) fluorescence assay revealed that b'xa' domain of PDI significantly inhibited αsyn aggregation. Furthermore, by using NMR titration, we observed that PDI bound to αsyn mainly through its hydrophobic cavity of the b' domain. Based on these findings, a docking model of PDI binding with αsyn was established and a possible mechanism of how PDI inhibits αsyn aggregation was proposed. Our work provides experimental evidences for understanding the inhibitory role of PDI in αsyn aggregation.
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