Transient oligomerization causing proteinopathies.

Abstract

Transient oligomerization is the self-assembly of multiple subunits of a protein hypothesized to have unique functions depending on the environmental conditions. The mechanism for this self-assembly and biological role remains elusive. It has been proposed that transient oligomerization may be introduced through evolution as a control for signaling pathways and act as a molecular switch to control biological function. Interestingly, amorphous aggregates may form from this protein assembly of wild-type proteins without the introduction of an amino acid substitution. The question then remains if transient oligomerization is a potential seed for aggregation or has a biological role as a molecular switch for signaling pathways. Our results show that our model protein can fold into a four-helix bundle that may form a trimeric complex depending on protein concentration in vitro. Molecular dynamic (MD) simulations combined with analytical ultracentrifugation (AUC) show that our model protein can form a trimeric complex, which needs to dissociate into monomeric states to bind to the receptor to activate the signaling cascade. Additionally, larger complexes have been observed that may form aggregates from its native state in vitro. Therefore, we hypothesize that the transformation of the trimeric complex may occur on pathway to aggregation or is the potential seed for aggregation. Investigating the molecular details of this phenomena will provide advancements in diseases regarding protein aggregation.