Heat shock response
The heat shock response (HSR) is a
Protein folding is already challenging due to the crowded intracellular space where aberrant interactions can arise; it becomes more difficult when environmental stressors can denature proteins and cause even more non-native folding to occur.[5] If the work by molecular chaperones is not enough to prevent incorrect folding, the protein may be degraded by the proteasome or autophagy to remove any potentially toxic aggregates.[6] Misfolded proteins, if left unchecked, can lead to aggregation that prevents the protein from moving into its proper conformation and eventually leads to plaque formation, which may be seen in various diseases.[7] Heat shock proteins induced by the HSR can help prevent protein aggregation that is associated with common neurodegenerative diseases such as Alzheimer's, Huntington's, or Parkinson's disease.[8]
Induction of the heat shock response
With the introduction of environmental stressors, the cell must be able to maintain proteostasis. Acute or chronic subjection to these harmful conditions elicits a cytoprotective response to promote stability to the proteome.
Molecular chaperones
Molecular chaperones are typically referred to as proteins that associate with and help other proteins reach a native conformation while not being present in the end state.[18] Chaperones bind to their substrate (i.e. a misfolded protein) in an ATP-dependent manner to perform a specific function.[19] Exposed hydrophobic residues are a major problem with regards to protein aggregation because they can interact with one another and form hydrophobic interactions.[20] It is the job of chaperones to prevent this aggregation by binding to the residues or providing proteins a "safe" environment to fold properly.[21] Heat shock proteins are also believed to play a role in the presentation of pieces of proteins (or peptides) on the cell surface to help the immune system recognize diseased cells.[22] The major HSPs involved in the HSR include HSP70, HSP90, and HSP60.[5] Chaperones include the HSP70s and HSP90s while HSP60s are considered to be chaperonins.[17]
The HSP70 chaperone family is the main HSP system within cells, playing a key role in translation, post-translation, prevention of aggregates and refolding of aggregated proteins.[23] When a nascent protein is being translated, HSP70 is able to associate with the hydrophobic regions of the protein to prevent faulty interactions until translation is complete.[24] Post-translational protein folding occurs in a cycle where the protein becomes bound/released from the chaperone allowing burying hydrophobic groups and aiding in overcoming the energy needed to fold in a timely fashion.[25] HSP70 plays a part in de-aggregating proteins using the aforementioned mechanism; the chaperone will bind to exposed hydrophobic residues and either partially or fully disassemble the protein, allowing HSP70 to assist in the proper refolding.[26] When proteins are beyond the point of refolding, HSP70s can help direct these potentially toxic aggregates to be degraded by the proteasome or through autophagy.[27] HSP90s are parallel to HSP70s with respect to the refolding or proteins and use in protein clearance.[4] One difference between the two HSPs is HSP90s ability to keep proteins in an unfolded yet stable configuration until a signal causes the protein to translocate and complete its folding.[24]
Sometimes, HSP70 is unable to effectively aid a protein in reaching its final 3-D structure; The main reason being the thermodynamic barriers for folding are too high for the chaperone to meet.[23] Because the intracellular space is very crowded, sometimes proteins need an isolated space to prevent aberrant interactions between other proteins, which is provided by chaperonins or HSP60s .[7] HSP60s are barrel shaped and suited to bind to the hydrophobic residues of proteins.[28] Once a cap binds to the chaperonin, the protein is free within the barrel to undergo hydrophobic collapse and reach a stable conformation.[29] Once the cap is removed, the protein can either be correctly folded and move on to perform its function or return to a HSP if it is still not folded accurately.[30] These chaperones function to remove aggregation and significantly speed up protein folding.[20]
Discovery
Discovery of the heat shock response is attributed to Italian geneticist
See also
References
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