Influence of the protein context on the propensity of polyglutamine tracts to trigger amyloid fibril formation

10 neurodegenerative diseases are associated with 10 proteins containing an expanded polyglutamine (polyQ) tract higher than a threshold of 35-45Q. This polyQ tracts trigger the aggregation of the proteins into amyloid fibrils that could play an important role in the disease. It is therefore necessary to investigate the aggregation properties of polyQ proteins. Accordingly, we have created model proteins made of the β-lactamase BlaP with 23 to 79Q inserted at positions 197 or 216. Their aggregation behaviour recapitulate those of disease-associated proteins (i.e. a threshold and the anticipation phenomenon). Moreover, the threshold depends on the structural integrity of BlaP (which applies constraints to the polyQ). In this work, we investigate the role of the protein context in the aggregation process using two techniques: QCM-D coupled with AFM. We observe that the native conformation of BlaP is the barrier for fibril formation, interfering with the nucleation step. Moreover, the protein environment of the polyQ (position 197 or 216) influences its propensity to form fibrils.