Protein Folding & Chaperones
Proteins are the workhorses of the living cell. They may differ in sequence, shape and function, but have in common that they all have to fold into specific three-dimensional structures, which are mandatory for proper function. Protein structures however are not rigid. Instead, proteins have a dynamic life style, which may involve unfolding and refolding, complex association and dissociation. Stress, but also many physiological events, require proteins to surrender their structure or to regain it at a later stage. Understanding protein folding within the complex environment of the living cell is a key question in modern biology and biological chemistry.
The cell controls many of these protein folding processes itself, others are forced onto the cell from the environment. Essential processes are events such as de novo synthesis of proteins, protein translocation into different compartments, or control of the activity of regulatory proteins. A major force from outside that damages protein structures is heat stress due to increase in temperature. Similar problems can be caused by chemical compounds such as solvents or heavy metals. DNA damage may lead indirectly to protein folding problems because the mutated proteins are often less stable than the wild type. Protein folding defects have important medical implications. They are associated e. g. with amyloid diseases such as Alzheimer and prion diseases such as Creutzfeldt-Jakob-Disease, but they are also a major cause of cancer due to destabilising mutations in the tumour suppressor protein p53. Likewise, several genetic disorders relate to protein folding defects: mutations in the CFTR protein that lead to its misfolding cause cystic fibrosis, while folding deficient LDL receptor protein variants cause familial hypercholesterolemia.
Every cell in every organism owns an arsenal of molecular chaperones to control folding and unfolding of proteins, or to react on protein unfolding during stress conditions. Most molecular chaperones are members of evolutionary conserved families: Hsp100, Hsp90, Hsp70 and their DnaJ (Hsp40) co-chaperones, the chaperonins Hsp60, and the small heat shock proteins (sHsp). Nearly all organisms have at least one homologue of each of these classes. Apart from chaperones also folding enzymes, such as peptidyl-prolyl cis-trans isomerases, assist protein folding in the cell. In contrast to prokaryotes, eukaryotes contain various organelles separated by lipid membranes. Translocation of fully folded proteins across membranes is often avoided. Instead, folding occurs in different compartments of the eukaryotic cell. The cytosol, mitochondria, chloroplasts in plants, and the Endoplasmic Reticulum (ER), each have their own ensemble of chaperones and folding enzymes. In addition, some chaperones exist that are exclusive to specific cell compartments or to bacteria.