Protein folding molecular chaperones

Sequence Comparisons Proteins called molecular chaperones (described in Chapter 4) assist in the process of protein folding. One class of chaperone found in organisms from bacteria to mammals is heat shock protein 90 (Hsp90). All Hsp90 chaperones contain a 10 amino acid signature sequence, which allows for ready identification of these proteins in sequence databases. Two representations of this signature sequence are shown below. 

In vivo, the correct assembly of proteins is guided by a family of cellular proteins termed molecular chaperones, e.g., heat shock protein (HSP), nuleoplasmins, and chaperonins. Chaperones bind to the intermediate that tends to aggregate, and either assembles the intermediate to the native state or renders the intermediate void of further reaction to form an aggregate. Normally, all proteins should fold without molecular chaperones. Proteins that tend to form aggregates, like those shown in the above mechanisms, bind to a chaperone to yield the native state. 

Ubiquitin, found in several cellular compartments (e.g., cytoplasm and the nucleus), belongs to a class of proteins referred to as stress proteins. Stress proteins, also called heat shock proteins (hsp), are so named because their syntheses are accelerated (and in some cases initiated) when cells encounter stress. (The name heat shock protein is misleading, because a variety of stressful conditions besides elevated temperature induce their synthesis.) Other stress proteins act as molecular chaperones, that is, they promote protein folding (p. 692). Heat shock proteins and molecular chaperones also play significant roles in protein transport and intermolecular interactions. 

Other larger molecules require the assistance of proteins called molecular chaperones to ensure correct folding. 

One of the most important aspects of protein synthesis is the folding of polypeptides into their biologically active conformations. Despite decades of investigation into the physical and chemical properties of polypeptide chains, the mechanism by which a primary sequence dictates the molecule s final conformation is unresolved. It has become increasingly clear that many proteins require molecular chaperones to fold into their final three-dimensional conformations. Protein mis-folding is now known to be an important feature of several human diseases, including Alzheimer s disease and Creutzfeld-Jacob disease. 

By the early 1990s, the basic paradigm that efficient protein folding in vivo depends on a set of highly conserved proteins termed molecular chaperones was well established (Cheng et at., 1989 Gething and... 

Hartl, F.U. Molecular chaperones in cellular protein folding. Nature 381 571-580, 1996. 

Molecular Chaperones Proteins That Help Fold Glohular Proteins... 

The way in which molecular chaperones interact with polypeptides during the folding process is not completely understood. What is clear is that chaperones bind effectively to the exposed hydrophobic regions of partially folded structures. These folding intermediates are less compact than the native folded proteins. They contain large amounts of secondary and even some tertiary... 

A number of different low molecular weight compounds are known to stablize proteins in their native conformation and, therefore, may be effective in correcting of protein folding abnormalities in vivo. Relevant compounds are iV-acetyl-L-lysine, L-camitine, taurine, betaine, ectoine, and hydroxy-ectoine [4]. Some of these chemical chaperones and pharmacological chaperones are already used in clinical trials to combat protein folding diseases, such as cystic fibrosis. 

Welch W, Brown CR (1996) Influence of molecular and chemical chaperones on protein folding. Cell Stress Chaperones 1 109-115... 

The efficient uptake of precursor proteins depends on their presentation in a translocation competent state. This is maintained in vivo by the specific interaction with a highly conserved group of proteins, the heat-shock or stress related proteins (hps70s). These act as molecular chaperones and interact with the proteins to maintain them in a correctly folded state, a process which is ATP dependent. 

Both the heat and cold shock response are universal and have been studied extensively. The major heat shock proteins (HSPs) are highly conserved. They are involved in the homeostatic adaptation of cells to harsh environmental conditions. Some act as molecular chaperones for protein folding, while others are involved in the processing of denatured polypeptides whose accumulation would be deleterious. The cold shock results in the transient induction of cold shock proteins (CSPs), which include a family of small acidic proteins carrying the cold shock domain. The CSPs appear to be involved in various cellular functions such as transcription, translation and DNA recombination. 

Molecular chaperones are able to temporarily stabihze unfolded or partially folded proteins and prevent inappropriate inter- and intramolecular interactions. They reduce the free concentration of aggregation-sensitive folding in-... 

Frydman J Folding of newly translated proteins in vivo The role of molecular chaperones. Annu Rev Biochem 2001 70 603. Radord S Protein folding Progress made and promises ahead. 

Exit from the ER may be the rate-limiting step in the secretory pathway. In this context, it has been found that certain proteins play a role in the assembly or proper folding of other proteins without themselves being components of the latter. Such proteins are called molecular chaperones a number of important properties of these proteins are listed in Table 46—5, and the names of some of particular importance in the ER are listed in Table 46-6. Basically, they stabilize unfolded... 

---