Abstract
S100 proteins assume a diversity of oligomeric states including large order self-assemblies, with an impact on protein structure and function. Previous work has uncovered that S100 proteins, including S100B, are prone to undergo β-aggregation under destabilizing conditions. This propensity is encoded in aggregation-prone regions (APR) mainly located in segments at the homodimer interface, and which are therefore mostly shielded from the solvent and from deleterious interactions, under native conditions. As in other systems, this characteristic may be used to develop peptides with pharmacological potential that selectively induce the aggregation of S100B through homotypic interactions with its APRs, resulting in functional inhibition through a loss of function. Here we report initial studies towards this goal. We applied the TANGO algorithm to identify specific APR segments in S100B helix IV and used this information to design and synthesize S100B-derived APR peptides. We then combined fluorescence spectroscopy, transmission electron microscopy, biolayer interferometry, and aggregation kinetics and determined that the synthetic peptides have strong aggregation propensity, interact with S100B, and may promote co-aggregation reactions. In this framework, we discuss the considerable potential of such APR-derived peptides to act pharmacologically over S100B in numerous physiological and pathological conditions, for instance as modifiers of the S100B interactome or as promoters of S100B inactivation by selective aggregation.
Highlights
S100 proteins are a family of EF-hand Ca2+-binding signaling proteins that have evolved in vertebrates to carry out a multitude of functions related to proliferation, differentiation, cell apoptosis, migration, energy metabolism, calcium homeostasis, and inflammation, under physiological and pathological conditions [1,2]
We present a preliminary study on the development of peptides containing tandem repeats of aggregation-prone regions (APR) derived from S100B that can selectively target the protein and modulate its function through selective co-aggregation
We showed that the designed APR peptides undergo amyloid-type aggregation, confirming that the APR segments from S100B undergo homotropic interactions that result in the formation of fibrillar materials
Summary
S100 proteins are a family of EF-hand Ca2+-binding signaling proteins that have evolved in vertebrates to carry out a multitude of functions related to proliferation, differentiation, cell apoptosis, migration, energy metabolism, calcium homeostasis, and inflammation, under physiological and pathological conditions [1,2]. It is useful to have drugs that are able to completely inhibit S100B activities but that are able to regulate its levels in cells In this respect, approaches based on the use of aggregation-prone peptides as tools to selectively inactive or modulate the levels of a given target protein, hold the potential to develop such sophisticated therapeutic biologics. These regions become solvent-exposed, homotypic interactions take place and β-aggregation evolves [20,21] We explore this property to design, synthesize, and characterize APR peptides inspired in S100B, as a first approach towards the future development of pharmacologically active biologics capable of targeting and modulating S100B levels and functions. We developed a mini library of three peptides inspired in APRs within helix IV of S100B, which we characterized with respect to their aggregation propensities, interaction with S100B, and in vitro co-aggregation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
