Unraveling the Heparin-Induced Protofibril Structure of GAPDH

Citotoxicity in Parkinson disease has been linked to an oligomeric arrangement of the protein α-synuclein (α-SN), which can alter the membrane permeability. In this work we could demonstrate the ability of heparin-induced Gliceraldehyde-3-phosphate dehydrogenase (GAPDH) aggregates to modulate the effect of oligomeric α-SN species on cell survival and membrane stability. From the GAPDH species formed after heparin addition, a cylinder-shaped protofibril species with an average length of 22 nm and a diameter of 12 nm are able to sequester α-SN oligomers. Using biocomputational techniques we obtained the first all-atom model of the GAPDH protofibril capable to satisfy experimental restrictions deduced from small angle X-ray scattering and mass spectrometry. We also propose a fibrillation pathway for the heparin-induced GAPDH aggregation. Upon heparin binding to GAPDH, the tetrameric state of the enzyme is lost and native-like dimer species appeared. The formed dimers are the building block of higher orders aggregates, which in a very fast way assemble to hexamers that piling up allowing the formation of the protofibrilar species.