Natural Spy Chaperone Mimic: Tailored Nanochaperone with Electrostatic–Hydrophobic Synergy To Enhance Protein Folding Regulation

Abstract

Protein folding regulation is of great significance for maintaining protein structures and biological functions. This fundamental process is assisted by molecular chaperones, which act in inhibiting undesired protein aggregation and facilitating misfolded protein refolding. Inspired by the unique structure and ingenious mechanisms of natural Spy chaperones, we innovate a nanochaperone-guided protein folding strategy by rationally designed nanochaperones (nChaps) with customizable surface structures and properties. In this strategy, the nChaps with tunable charged surfaces can first rapidly capture different client proteins through long-range electrostatic attraction, similar to Spy. Subsequently, the captured proteins can be dynamically bound into the Spy-mimetic hydrophobic microdomains via short-range hydrophobic interactions. As a result, the client proteins are sequestered and stabilized in the chaperone-mimicking confined spaces on the surface of nChaps, thereby facilitating dynamic regulation of protein folding through an electrostatic-hydrophobic synergy mechanism. Moreover, benefiting from the adjustable charge and multiple hydrophobic microdomains, this biomimetic nChap potentiates protein stability at harsh temperatures and long-term storage, which is hardly achieved by natural Spy. Additionally, this strategy is applicable to 9 different proteins with varying isoelectric points and molecular weights, showing superior generality than Spy. Therefore, this work provides new perspectives in developing an advanced strategy for enhanced protein folding regulation.