Cedric Eichmann, Switzerland
ETH Zurich Department of Chemistry and Applied BiosciencesAuthor Of 1 Presentation
STRUCTURE ACTIVITY RELATIONSHIP OF A-SYNUCLEIN IN CELLS
Abstract
Aims
It is the aim to study the mechanisms of a-synuclein aggregation in cells at atomic resolution to obtain detailed mechanistic insights of the kinetic aggregtaion process including the cellular players involved. For this a structure activity relationship using in vitro and in cell NMR of a-synuclein is established.
Methods
in cell NMR; solution and solid state NMR; cryo EM; recombinant proteins; kinetics; cell biology
Results
It is known and further demonstrated that in cells (and in vitro) monomeric a-synuclein is not entirely unfolded attributed to the interaction between its positively charged N-terminus and its negatively charged C-terminus, which protects from aggregation. Furthermore, a-synuclein is interacting transiently with protein chaperones (such as HSP90), which regulate a-synuclein function and further interfere with aggregation. Upon down regulation of HSP90 a-synuclein is dislocated to the mitochondria where it unfolds further by transient interaction with a positively charged protein AK2 losing the intra-synuclein aggregation protection enabling protein aggregation. Once fibrils are present they interact with monomeric a-synuclein transiently through inter-molecular interaction between the negatively charged C-terminus of the fibrils and the N-terminal positive charged monomer, which again yields an unfolded aggregation-prone monomer yielding the secondary nucleation process, which is a very important acceleration component of the aggregation process.
Burmann et al Nature 2020 577:127-132.
Conclusions
The detailed structural studies show one mechanism of a-synuclein aggregation in cells at near atomic resolution elucidating thereby that the unfolding of a-synuclein is key for aggregation both at the initial step through interaction with other cellular players or during the secondary nucleation mechanism of the aggregation kinetics.