Molecular chaperones

Chaperones are unique remodeling proteins that participate in a great number of intracellular processes and are involved in the correction of protein structure, the prevention of the aggregation of misfolded proteins, the destruction of protein aggregates, and also the unfolding of native protein targets for their translocation across a membrane. In addition to this, chaperones assist in the dismantling of active oligomers into inactive unfolded monomers for their subsequent proteolytic degradation and the assembly of folded subunits into protein assemblies and specific complexes. Data on the structure and functioning of molecular chaperones from five basic families are summarized in the review.     

Molecular chaperones: pathways and networks

Some proteins synthesized by growing eukaryotic cells are transferred along unidirectional pathways of molecular chaperones until the risk of aggregation has decreased and they can be released safely. Mature proteins denatured by stress may instead be handled by chaperones acting in branched, reversible networks.     

Molecular chaperones: new proteins--new functions]

A new class of cellular proteins named "molecular chaperones" has been described recently. Chaperones prevent from improper interactions either within or between polypeptide chains, which could produce incorrect structures. Chaperones assist in assembly or disassembly of oligomeric structures and in protein transport across membranes. There are three conservative families of chaperones and a few unrelated members. Some of them appeared to be stress proteins with yet unknown function. Mechanism of action and specificity of chaperone binding are under investigation now.     

Molecular chaperones: Inside and outside the Anfinsen cage

The GroEL/GroES chaperonin system acts as a passive anti-aggregation cage for refolding rubisco and rhodanese, and not as an active unfolding device. Refolding aconitase is too large to enter the cage but reversible binding to GroEL reduces its aggregration. Unexpectedly, confinement in the cage increases the rate of refolding of rubisco, but not rhodanese.     

Molecular chaperones: structure of a protein disaggregase

The ring-forming molecular chaperone Hsp104/ClpB is a member of the AAA+ protein family which rescues proteins from aggregated states. The newly determined crystal structure of ClpB provides new insights into the mechanism of protein disaggregation, suggesting a crowbar activity mediated by a unique coiled-coil domain.     

Molecular chaperones: small heat shock proteins in the limelight

Small heat shock proteins have been the Cinderellas of the molecular chaperone world, but now the crystal structure of a small heat shock protein has been solved and mutation of two human homologues implicated in genetic disease. Intermediate filaments appear to be one of the key targets of their chaperone activity.     

Molecular chaperones: the busy life of Hsp90.

The heat shock protein Hsp90 is a molecular chaperone which assists the refolding of misfolded proteins, but also has highly selective functions in normal metabolism. These dual functions enable Hsp90 to connect environmental conditions with developmental processes and to buffer genetic changes.     

Molecular chaperones: assisting assembly in addition to folding

The common perception that molecular chaperones are involved primarily with assisting the folding of newly synthesized and stress-denatured polypeptide chains ignores the fact that this term was invented to describe the function of a protein that assists the assembly of folded subunits into oligomeric structures and only later was extended to embrace protein folding. Recent work has clarified the role of nuclear chaperones in the assembly of nucleosomes and has identified a cytosolic chaperone required for mammalian proteasome assembly, suggesting that the formation of other oligomeric complexes might be assisted by chaperones.     

Molecular chaperones and selection against mutations

Background  

Molecular chaperones help to restore the native states of proteins after their destabilization by external stress. It has been proposed that another function of chaperones is to maintain the activity of proteins destabilized by mutation, weakening the selection against suboptimal protein variants. This would allow for the accumulation of genetic variation which could then be exposed during environmental perturbation and facilitate rapid adaptation.     

Molecular chaperones in cellular protein folding

The discovery of “molecular chaperones” has dramatically changed our concept of cellular protein folding. Rather than folding spontaneously, most newly synthesized polypeptide chains seem to acquire their native conformation in a reaction mediated by these versatile helper proteins. Understanding the structure and function of molecular chaperones is likely to yield useful applications for medicine and biotechnology in the future.     

Molecular chaperones in protein quality control

Proteins must fold into their correct three-dimensional conformation in order to attain their biological function. Conversely, protein aggregation and misfolding are primary contributors to many devastating human diseases, such as prion-mediated infections, Alzheimer's disease, type II diabetes and cystic fibrosis. While the native conformation of a polypeptide is encoded within its primary amino acid sequence and is sufficient for protein folding in vitro, the situation in vivo is more complex. Inside the cell, proteins are synthesized or folded continuously; a process that is greatly assisted by molecular chaperones. Molecular chaperones are a group of structurally diverse and mechanistically distinct proteins that either promote folding or prevent the aggregation of other proteins. With our increasing understanding of the proteome, it is becoming clear that the number of proteins that can be classified as molecular chaperones is increasing steadily. Many of these proteins have novel but essential cellular functions that differ from that of more "conventional" chaperones, such as Hsp70 and the GroE system. This review focuses on the emerging role of molecular chaperones in protein quality control, i.e. the mechanism that rids the cell of misfolded or incompletely synthesized polypeptides that otherwise would interfere with normal cellular function.     

Molecular chaperones and protein quality control

In living cells, both newly made and preexisting polypeptide chains are at constant risk for misfolding and aggregation. In accordance with the wide diversity of misfolded forms, elaborate quality-control strategies have evolved to counter these inevitable mishaps. Recent reports describe the removal of aggregates from the cytosol; reveal mechanisms for protein quality control in the endoplasmic reticulum; and provide new insight into two classes of molecular chaperones, the Hsp70 system and the AAA+ (Hsp100) unfoldases.