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α-Synuclein (α-syn) is the main protein component of Lewy bodies, the major pathological hallmarks of Parkinson's disease (PD). C-terminally truncated α-syn is found in the brain of PD patients, reduces cell viability and tends to form fibrils. Nevertheless, little is known about the mechanisms underlying the role of C-terminal truncation on the cytotoxicity and aggregation of α-syn. Here, we use nuclear magnetic resonance spectroscopy to show that the truncation alters α-syn conformation, resulting in an attractive interaction of the N-terminus with membranes and molecular chaperone, protein disulfide isomerase (PDI). The truncated protein is more toxic to mitochondria than full-length protein and diminishes the effect of PDI on α-syn fibrillation. Our findings reveal a modulatory role for the C-terminus in the cytotoxicity and aggregation of α-syn by interfering with the N-terminus binding to membranes and chaperone, and provide a molecular basis for the pathological role of C-terminal truncation in PD pathogenesis. C-terminal truncation of a-syn results in a more extended and exposed conformation, providing further insight into the pathological role of this truncation event in the progression of Parkinson's disease. [ABSTRACT FROM AUTHOR]

Human protein disulfide isomerase (PDI), a protein containing 4 domains a, b, b′, a′, disordered x linker and C-terminus, plays critical roles in disulfide bond reactions and proper protein folding in the endoplasmic reticulum. The bb′ domain contributes to client binding, the a, a′ domain catalyse the rearrangement of the disulfide bonds. The x linker and a′ domain were the main dynamics region for full-length PDI and the b′xa′ construct has the minimum functional domain within full-length PDI. Herein, we report a new preparation strategy with 1, 6-hexandiol and backbone NMR chemical shift assignments for the monomer b′xa′ domain. [ABSTRACT FROM AUTHOR]