Chaperoning roles of macromolecules interacting with proteins in vivo

Abstract

The principles obtained from studies on molecular chaperones have provided explanations for the assisted protein folding in vivo. However, the majority of proteins can fold without the assistance of the known molecular chaperones, and little attention has been paid to the potential chaperoning roles of other macromolecules. During protein biogenesis and folding, newly synthesized polypeptide chains interact with a variety of macromolecules, including ribosomes, RNAs, cytoskeleton, lipid bilayer, proteolytic system, etc. In general, the hydrophobic interactions between molecular chaperones and their substrates have been widely believed to be mainly responsible for the substrate stabilization against aggregation. Emerging evidence now indicates that other features of macromolecules such as their surface charges, probably resulting in electrostatic repulsions, and steric hindrance, could play a key role in the stabilization of their linked proteins against aggregation. Such stabilizing mechanisms are expected to give new insights into our understanding of the chaperoning functions for de novo protein folding. In this review, we will discuss the possible chaperoning roles of these macromolecules in de novo folding, based on their charge and steric features.

Keywords: aggregation; de novo folding; hydrophobic interactions; macromolecules; molecular chaperones; stabilization; steric hindrance; surface charges.

Figure 1.

A model for how N-terminal domains solubilize their linked domains. The blue, gray, and wrinkled spheres represent the folded N- and C-terminal domains, and incompletely folded C-terminal domains, respectively. The red spots on wrinkled spheres indicate the exposed regions involved in the intermolecular interactions. Thick arrows represent the shift from the oligomeric state to the monomeric state (boxed) of proteins driven by the electrostatic repulsions and steric hindrance of folded N-terminal domains. (Reproduced from Reference [49]).

Figure 2.

A schematic illustration of substrate-stabilizing factors of macromolecules and their correlation with the size of the macromolecule. Here, an example of a soluble macromolecule, DnaK, with varying radius r and constant surface charge density and its bound aggregation-prone protein are represented as sphere A and B, respectively. The potential factors of sphere A such as electrostatic repulsions, steric hindrance, and hydrophobic shielding are considered as a function of the radius r of sphere A. The hatched area represents the surfaces inaccessible to other B by the steric masking of the corresponding A. (Adapted from Reference [58]).

Figure 3.

A model for RNA binding-mediated protein folding. Both the folded RNA-binding domain (RBD) at the N-terminal position and bound RNA prevent inter-molecular interactions among folding intermediates, leading to soluble expression and favoring kinetic network into productive folding. The number of black bars (| and ||) represents the extent of aggregation inhibition. (Reproduced from Reference [67]).