Role of Molecular Chaperones on Structural Folding, Biological Functions, and Drug Interactions of Client Proteins

From a social perspective, the word chaperone refers to a matron who used to accompany young people in public, especially ladies, and supervise them at a social gathering to ensure proper behavior. Similarly, those proteins that assist others in their proper folding and biological functions are also referred to as chaperones. During the late ‘70s, it was coined the term ‘molecular chaperones’ to make reference to the ability of nucleoplasmin to prevent the aggregation of histones with DNA during the assembly of nucleosomes. As a consequence, this nomenclature was extended to all proteins able to mediate the post-translational assembly of protein complexes. Although the primary concept of molecular chaperone was related to its ability to ensure the correct folding of newly synthesized peptides and refolding of stress-denatured proteins, it should be noted that chaperones are also involved in essential and more sophisticated functions such as promoting the correct assembly of oligomeric complexes. One of the most remarkable examples for this special feature is the ability of a particular subfamily of molecular chaperones, the heat-shock proteins, to assist the proper assembly of steroid receptors with chaperones and co-chaperones. This important feature permits the binding of steroids to activate isoform of the receptor, which functions as a ligand-dependent transcription factor.

The term ‘heat-shock protein’ stems from the original observation that heat-stress greatly enhances the production of this particular class of molecular chaperones. This means that all heat-shock proteins are molecular chaperones, but not all molecular chaperones are necessarily heat-shock proteins. Temperature is not the only stimulus able to induce heat-shock proteins. Upon the onset of several environmental types of stress or due to the exposure to damaging and extreme insults, the cells increase dramatically the production of molecular chaperones, which play prominent roles in many of the most basic cellular processes by stabilizing unfolded or misfolded peptides, giving the cell time to repair or re-synthesize damaged proteins. In addition to commanding the proper folding of a factor exposed to an environmental injury, many chaperones are also related to other key functions such as enzyme activity, cytoskeletal architecture, nuclear organization, protein trafficking, transcriptional regulation, epigenetic alterations of gene expression and, even more intriguingly, heritable alterations in chromatin state.