Massively parallel genetic perturbation reveals the energetic architecture of an amyloid beta nucleation reaction.

ABSTRACT: Amyloid protein aggregates are pathological hallmarks of more than fifty human diseases but how soluble proteins nucleate to form amyloids is poorly understood. Here we use combinatorial mutagenesis, a kinetic selection assay, and machine learning to massively perturb the energetics of the nucleation reaction of amyloid beta (Aβ42), the protein that aggregates in Alzheimer's disease. In total, we quantify the nucleation rates of >140,000 variants of Aβ42. This allows us to accurately quantify the changes in reaction activation energy for all possible amino acid substitutions in a protein for the first time and, in addition, to quantify >600 energetic interactions between mutations. The data reveal the simple and interpretable genetic architecture of an amyloid nucleation reaction. Striking

SUBMITTER: Arutyunyan A 

PROVIDER: S-EPMC11291115 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature