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Review
. 2015 Jul 28;16(8):17193-230.
doi: 10.3390/ijms160817193.

Protein Folding and Mechanisms of Proteostasis

José Fernando Díaz-Villanueva  1 , Raúl Díaz-Molina  2 , Victor García-González  3
Affiliations
Review

Protein Folding and Mechanisms of Proteostasis

José Fernando Díaz-Villanueva et al. Int J Mol Sci. .

Abstract

Highly sophisticated mechanisms that modulate protein structure and function, which involve synthesis and degradation, have evolved to maintain cellular homeostasis. Perturbations in these mechanisms can lead to protein dysfunction as well as deleterious cell processes. Therefore in recent years the etiology of a great number of diseases has been attributed to failures in mechanisms that modulate protein structure. Interconnections among metabolic and cell signaling pathways are critical for homeostasis to converge on mechanisms associated with protein folding as well as for the preservation of the native structure of proteins. For instance, imbalances in secretory protein synthesis pathways lead to a condition known as endoplasmic reticulum (ER) stress which elicits the adaptive unfolded protein response (UPR). Therefore, taking this into consideration, a key part of this paper is developed around the protein folding phenomenon, and cellular mechanisms which support this pivotal condition. We provide an overview of chaperone protein function, UPR via, spatial compartmentalization of protein folding, proteasome role, autophagy, as well as the intertwining between these processes. Several diseases are known to have a molecular etiology in the malfunction of mechanisms responsible for protein folding and in the shielding of native structure, phenomena which ultimately lead to misfolded protein accumulation. This review centers on our current knowledge about pathways that modulate protein folding, and cell responses involved in protein homeostasis.

Keywords: folding; misfolding; proteins; proteostasis.

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Figures

Figure 1
Figure 1
Molecular and cellular mechanisms to maintain native protein structure. The vertical arrows indicate the mechanisms which cells employ to counteract alterations in native protein structure, during their lifetime (horizontal arrow). When the cellular machinery designed to control widespread protein misfolding or aggregation fails, apoptosis ensues. When apoptosis cannot restrict the systemic spread of protein misfolding, chronic diseases originate (red arrow).
Figure 2
Figure 2
Cell mechanisms that control protein structure. Alterations in protein structure during folding can result in anomalous interactions with inner membranes through the exposition of hydrophobic surfaces. Cellular mechanisms, such as proteasome activity and autophagy, could reduce toxic effects of these molecules, and ultimately prevent cell damage. Likewise, these processes occur during physiological protein turnover (Adapted from [6]).
Figure 3
Figure 3
Activation of the inositol requiring enzyme 1 (IRE1) branch of the unfolded protein response (UPR) pathway is tightly controlled. (A) Schematic representation of IRE1 oligomerization and cellular response induced by unfolded proteins. The structure employed was obtained from the protein data bank (PDB) access code: 3fbv; (B) Uncontrolled protein aggregation in the formation of amyloid fibrils; (C) Effect of the overactivation of IRE1 branch on cellular homeostasis. Adapted from reference [141]; (D) Structural representation of IRE1 with a focus on the surface of interaction between monomers. Inset: sterol binding site, with two bound molecules of quercetin. Structure was obtained from PDB access code: 3LJ0.
Figure 4
Figure 4
Scheme of the 26S proteasome. Proteins that make up the base and lid of the 19S regulatory subunit are shown. The cylindrical portion of the 20S catalytic subunit is shown in an open conformation, showing the arrangement of α and β proteins identified in orange and blue, respectively (Adapted from [167]).
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