In agreement with these data, AGGRESCAN shows that inner membrane proteins possess the highest aggregation propensities of all bacterial proteins (Figure 9C).
Mutation of Trp377 resulted in the highest aggregation observed (lane 6), some of which could not be dissociated under denaturing conditions (Fig. 9B, lane 6).
The main intrinsic properties that determine protein aggregation have been defined and different computational approximations [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20] have exploited them to predict with reasonable accuracy the regions of proteins with the highest aggregation propensity, also called hot spots, as well as the overall protein aggregation propensity.
However, when mutations occur at E100, the mutant with a larger increase in net negative charge has the highest aggregation propensity (E100K versus G).
Using FT, both of our model proteins showed the highest aggregation propensity, which illustrated the impact of perturbation on protein stability (Table 1).
Our results can explain both the higher aggregation propensity of Aβ42 and the importance of Aβ42 to Aβ40 ratio in the pathogenesis of Alzheimer's disease.
For proof of concept, we designed a series of peptides based on the high aggregation prone C-terminus of Aβ42, which is associated with Alzheimer's disease.
Furthermore, we found that the high aggregation propensity of one of the edge strands, βI, promotes dimerisation of the native structure rather than misfolding and aggregation since the structure of βI is stabilised by the presence of a disulfide bond.
Evaluation under polarized light showed both areas of high birefringence in the newly formed bone, indicative of the high aggregation and organization of collagen bundles of mature lamellar bone, as well as areas of low birefringence, indicative of the disorganized collagen bundles of immature bone.
Our screen was biased towards detecting suppressors due to the high aggregation propensity of our cell line.
