In vivo aspects of protein folding and quality control

BACKGROUND Proteins are synthesized on ribosomes as linear chains of amino acids and must fold into unique three-dimensional structures to fulfill their biological functions. Protein folding is intrinsically error-prone, and how it is accomplished efficiently represents a problem of great biological and medical importance. During folding, the nascent polypeptide must navigate a complex energy landscape. As a result, misfolded molecules may accumulate that expose hydrophobic amino acid residues and thus are in danger of forming potentially toxic aggregates. To ensure efficient folding and prevent aggregation, cells in all domains of life express various classes of proteins called molecular chaperones. These proteins receive the nascent polypeptide chain emerging from the ribosome and guide it along a productive folding pathway. Because proteins are structurally dynamic, constant surveillance of the proteome by an integrated network of chaperones and protein degradation machineries, the proteostasis network (PN), is required to maintain protein homeostasis in a range of external and endogenous stress conditions. ADVANCES Over the past decade, we have gained substantial new insight into the overall behavior of the PN and the molecular mechanics of its components. Advances in structural biology and biophysical approaches have allowed chaperone mechanisms to be interrogated at an unprecedented level of detail. Recent work has provided fascinating insight into the process of protein folding on the ribosome and revealed how highly allosteric chaperones such as the heat shock protein 70 (Hsp70), Hsp90, and chaperonin systems modulate the folding energy landscapes of their protein clients. Studies of chaperone systems from bacteria and eukaryotes have revealed common principles underlying the organization of chaperone networks in different domains of life. Recently, we have begun to appreciate the relative complexity of eukaryotic chaperones and are starting to understand how eukaryotes deal with the challenge of folding a large proteome enriched in multidomain proteins. At the cellular level, the response of the PN to conformational stress, aging, and diseases of aberrant protein folding has been an area of intense investigation. Importantly, the capacity of the PN declines during aging and this leads to dysfunction of specific cell types and tissues, rendering the organism susceptible to chronic diseases. Among these, neurodegenerative syndromes associated with protein aggregation are increasingly prevalent in the aging human population. Notably, the accumulation of toxic protein aggregates is both a consequence and a cause of PN decline, driving a vicious cycle that ultimately leads to proteostasis collapse. OUTLOOK A new view of protein folding is emerging, whereby the energy landscapes that proteins navigate during folding in vivo may differ substantially from those observed during refolding in vitro. From the ribosome through to the major chaperone systems, the nascent protein interacts with factors that modulate its folding pathway. Future work should focus on obtaining the high-resolution structural and kinetic information necessary to define the pathways of protein folding during translation, and in association with molecular chaperones. Organisms have evolved various mechanisms to deal with misfolded and aggregated proteins to maintain proteostasis. It is becoming increasingly clear that besides removing these proteins by degradation, cells also strategically sequester them into transient or stable aggregates, often in defined cellular locations. Much remains to be understood about how this cellular decision-making occurs at a molecular level and how dysregulation of these mechanisms leads to proteotoxicity. From a medical perspective, the intimate relationship between proteostasis and disease, aging, and neurodegeneration makes components of the PN logical drug targets, with the goal of promoting healthy aging. Pharmacological manipulation of the PN will require a detailed understanding of how the network responds to perturbation and how its different components cooperate. Molecular chaperones are key players in the cellular proteostasis network and serve to maintain a balanced proteome. They promote the folding of newly synthesized proteins, function in conformational maintenance, and prevent potentially toxic off-pathway aggregation. Chaperones also cooperate with other components of the proteostasis network, such as the proteasome system and autophagy, in the removal of terminally misfolded and aggregated proteins through proteolytic degradation. Most proteins must fold into unique three-dimensional structures to perform their biological functions. In the crowded cellular environment, newly synthesized proteins are at risk of misfolding and forming toxic aggregate species. To ensure efficient folding, different classes of molecular chaperones receive the nascent protein chain emerging from the ribosome and guide it along a productive folding pathway. Because proteins are structurally dynamic, constant surveillance of the proteome by an integrated network of chaperones and protein degradation machineries is required to maintain protein homeostasis (proteostasis). The capacity of this proteostasis network declines during aging, facilitating neurodegeneration and other chronic diseases associated with protein aggregation. Understanding the proteostasis network holds the promise of identifying targets for pharmacological intervention in these pathologies.