The structure of molecular chaperones
Under stress conditions such as temperature changes or UV light, our cells respond by expressing a family of proteins known as heat shock proteins (HSPs). Many members of this family act as chaperones, in other words they help to fold or refold proteins that were damaged during stress. This mechanism prohibits protein aggregation that can lead to various pathological situations such as Alzheimer's disease. Small HSPs are a new addition to the family of HSPs and act when key members of the family such as HSP90 are inactive. This first line of activity against protein aggregation has received great interest and emerging roles of sHSPs include tumour protection against chemotherapeutic reagents. In addition, mutations have been linked to inherited peripheral neuropathies, myofibrillar myopathy and cataract. The EU-funded SHSPCOMPLEX (Structural studies of human small heat shock proteins and their complexes) project focused on HSPB6 and the delineation of its structure. Since it was not possible to obtain the crystal structure of the full length protein, scientists followed a hybrid approach. They expressed in E.coli a fragment of the protein that corresponds to the alpha crystalline domain and solved its three-dimensional structure. Various mutants of the proteins were also employed to extend the atomic resolution of the HSPB6 structure. Using specific algorithms, scientists were able to obtain all biologically relevant models of HSPB6. They concluded that HSPB6 acts as a dimer in solution and its activity was highly dependent on a conserved stretch of residues. They were also able to pinpoint a part located at the N-terminal region of this protein that was necessary to prevent aggregation of a number of standard substrates. During the course of the project, dimeric members of the sHSP superfamily were also found to be present in bacteria and plants. This reinforces the importance of these molecules across species and further extends the applicability of the SHSPCOMPLEX results. Whether as a therapeutic strategy against cancer or as an approach to counteract the impact of stress, manipulation of the sHSP family of proteins could prove beneficial.
Keywords
Heat shock proteins, chaperones, protein aggregation, HSPB6
