Other future challenges will involve deciphering the folding mechanisms of large proteins and protein complexes, including macromolecular machines with multiple subunits, cofactors and nucleic acids, that perform many of the essential functions of life. Modifications such as phosphorylation, glycosylation, methylation and lipidation that extend the functional repertoire of proteins in the context of their folding landscape must also be tackled.
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The exploration of how membrane proteins fold is a subject in its infancy biophysically, and there are many challenges ahead in unpicking this complex folding environment. In addition, we need to expand our understanding of folding in the cell to a quantitative level. In the cellular environment, folding commonly involves molecular chaperones and may be challenged by stochastic events such as aggregation. Current research is focusing on developing and applying biophysical techniques to the in vivo environment, with the ultimate goal of a quantitative understanding of the folding landscape in the cell.
In the s, the field of molecular chaperones witnessed a jump-start, with many seminal discoveries of unexpected traits and diversity. This led to the emergence of new concepts that stimulated the entire field of protein folding.
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An example in case is the finding that in the bacterial cytosol some polypeptide chains fold in splendid isolation one by one within the confined GroEL chamber. The excitement over the uncharted territory opening up and the rapidly growing list of functionally diverse chaperones put the concept of assisted folding in the limelight and, for some, spontaneous folding was 'old school'. In the past years, the pendulum has been swinging back and, by now, may have reached middle ground.
The present evidence suggests that, also in the living cell, most proteins fold spontaneously, but there is a certain fraction of proteins that are addicted to chaperone assistance to reach or maintain their functional states. And, as Anfinsen rightly pointed out many years ago, environmental conditions are a key factor in this context: under stress conditions, such as heat shock, chaperone dependence will prevail.
Despite all the progress on chaperone structure and function, we still lack a detailed description of how a chaperone affects client protein conformation during assisted folding. What happens to a protein while it is processed by a chaperone? We got first glimpses for proteins in GroE complexes, but for all the other chaperones information is largely lacking.
This is a technically challenging area, but certainly one that is central to propelling the field to the next level.
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Biophysics and cell biology must join hands to achieve this goal. On the other hand, we need a bird's eye view of chaperone action, that is, to watch the different chaperone proteins present in the same ball park functioning simultaneously. Are they team players with defined functions? Do they talk to each other? Are they organized as relay teams? Is there competition? How flexible is this system? How are viruses and other pathogens exploiting chaperone function?
Given the speed with which this field evolved, it will not be long until we get the first answers—and new unexpected questions. Forty years ago, the Levinthal paradox hypothesized that the process of protein folding would require a time longer than the age of the universe if it occurred via a random search of contacts, postulating the existence of well-defined pathways with intermediates guiding the search to the fully native state.
This reasoning led the field to search for folding intermediates. As more and more details were collected on the structure and dynamics of intermediates, it also became clear that some of them were off-pathway species. Moreover, the new view of protein folding has also clarified that stable intermediates forming on the energy landscape are not necessary for folding to be efficient. While these conclusions were reached, investigators started to realize that proteins have an intrinsic potential to form misfolded protein aggregates, such as amyloid-like fibrils or other structured aggregates, and that this propensity is particularly high for fully or partially unfolded states, such as those formed during folding.
Protein-folding intermediates can have a role that was unexpected until 10 years ago, that is, to modulate the propensity of a protein to aggregate. As partially folded states can be more or less amyloidogenic than fully unfolded states, depending on conditions and the nature of the structure present inside them, the formation of intermediates along the folding reaction, their stability and on- or off-pathway nature can depend on their ability to counteract aggregation.
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This is a major challenge that the field has to face in conjunction with that of protein misfolding. A full description of the energy landscape of proteins that takes into account both folding and aggregation can help us to understand the shape of a particular energy landscape. The intimate link between folding and aggregation is also essential for our ambition to clarify protein folding in vivo. Chaperones are not species devoted only to helping the intramolecular search of native contacts within a protein; they also inhibit intermolecular contacts between distinct folding molecules. An understanding of the fascinating mechanism by which the protein-folding machinery works in vivo cannot prescind from this concept.
Protein quality-control factors act in integrated networks to maintain non-native proteins at optimal levels for proper folding and assembly. This is crucial for survival, as escape of misfolded proteins from surveillance leads to the accumulation of toxic protein species and a number of protein conformational diseases.
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Molecular chaperones protect cells from such pathologies by suppressing protein aggregation, promoting protein refolding and even facilitating protein aggregation. All these cellular efforts aim to limit the accumulation of toxic protein oligomers implicated in neurodegenerative diseases as agents of death. Emerging data indicate that specific HspHsp40 chaperone pairs also function as substrate selectors for a network of multisubunit quality-control E3 ubiquitin ligases that target misfolded proteins for degradation. Chaperone-dependent ubiquitin ligases are localized to the cytoplasmic face of the endoplasmic reticulum, the cytosol and the nucleus.
In addition, we are just realizing that there are also single-subunit quality-control E3s with built-in chaperone domains that function independently of Hsp70 to directly recognize and target misfolded proteins for degradation.
The CHIP-Hsp70 multisubunit complex was the first chaperone-dependent E3 ubiquitin ligase identified, and elevation of CHIP activity suppresses toxicity of neurodegenerative proteins to different degrees. Molecular chaperones have clear preference for non-native proteins that show different aspects of non-native protein structure. Therefore, it is possible that members of the chaperone-dependent ubiquitin-ligase network preferentially recognize different disease proteins. If true, it is possible that fluctuations in the expression pattern of chaperone-dependent ubiquitin-ligase family members are related to the selective vulnerability of neurons to specific disease proteins.
Tests of these concepts will position the field to develop compounds that modulate activity of individual chaperone-dependent ubiquitin ligases to treat protein conformational disease. One of the big intriguing issues in the field is that, even after all these years of intensive research, we still don't know what chaperones really do in the cell.
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