Molecular biology and immunology for clinicians 18: Heat shock proteins/chaperonins

Heat shock proteins are a highly conserved set of families of proteins produced after a variety of stresses, both pathologic and physiologic. They are made by all living cells; all cells use basically the same mechanisms to deal with profound stresses. The second remarkable feature of the heat shock proteins is that their sequence and structure are remarkably conserved across broad stretches of evolutionary history: from Escherichia coli to Homo sapiens, heat shock proteins have not changed a lot! Finally, as alluded to previously, heat shock proteins are involved in physiologic functions as well, such as keeping hormonal and antigen receptors and cell cycle-related proteins in their appropriate state of readiness or inactivity, awaiting the ligand that will activate them. Polypeptide chains emerge from the ribosome as a straight chain that then assumes a tertiary structure (e.g., alpha helices, beta-pleated sheets, disulfide and hydrogen bonds). The process of folding into this final structure may require help because the required tertiary structure may not be the one into which the polypeptide chain would fold if left to its own devices. Scaffolding may be needed to coax the polypeptide to fold into its proper functional final structure, which may not be the morphology most thermodynamically favored. The polypeptide chain contains a series of potentially interactive surfaces (with other sections of the polypeptide or with other proteins in the cell), just as a receptor has at least one potentially interactive surface. Heat shock proteins guard these potentially interactive surfaces from unwanted interactions with extraneous and irrelevant "suitors" and may help coax the protein into the desired interaction. The alternative to this assistance may be that the protein folds into a useless blob or a shape that is not optimal for its intended use; such misfolded proteins are degraded by normal housekeeping functions of the cell. The highly conserved nature of heat shock proteins means that the immune response to heat shock proteins of pathogens or malignant cells may recognize and then react with host heat shock proteins and produce autoimmune disease.