Assembly chaperones: a perspective.

The historical origins and current interpretation of the molecular chaperone concept are presented, with the emphasis on the distinction between folding chaperones and assembly chaperones. Definitions of some basic terms in this field are offered and misconceptions pointed out. Two examples of assembly chaperone are discussed in more detail: the role of numerous histone chaperones in fundamental nuclear processes and the co-operation of assembly chaperones with folding chaperones in the production of the world's most important enzyme.

Chaperones: needed for both the good times and the bad times.

In this issue, we explore the assembly roles of protein chaperones, mainly through the portal of their associated human diseases (e.g. cardiomyopathy, cataract, neurodegeneration, cancer and neuropathy). There is a diversity to chaperone function that goes beyond the current emphasis in the scientific literature on their undoubted roles in protein folding and refolding. The focus on chaperone-mediated protein folding needs to be broadened by the original Laskey discovery that a chaperone assists the assembly of an oligomeric structure, the nucleosome, and the subsequent suggestion by Ellis that other chaperones may function in assembly processes, as well as in folding. There have been a number of recent discoveries that extend this relatively neglected aspect of chaperone biology to include proteostasis, maintenance of the cellular redox potential, genome stability, transcriptional regulation and cytoskeletal dynamics. So central are these processes that we propose that chaperones stand at the crossroads of life and death because they mediate essential functions, not only during the bad times, but also in the good times. We suggest that chaperones facilitate the success of a species, and hence the evolution of individuals within populations, because of their contributions to so many key cellular processes, of which protein folding is only one.

The chaperone function: meanings and myths.

What are molecular chaperones and how should we think about them? We propose that it is better to think in terms of a chaperone function rather than in terms of chaperone molecules. We define the chaperone function as the prevention or reversal of incorrect interactions that may occur when reactive macromolecular surfaces are transiently exposed to the intracellular environment. We suggest that this function is a distinct and essential cellular function, mediated by many different proteins. Chaperones have evolved to reduce, by a variety of mechanisms, the aggregation of proteins into non-functional, and sometimes cytotoxic, structures. Chaperones may also have evolved to have additional roles. A cellular or extracellular event mediated by a chaperone protein is not necessarily a consequence of that protein's chaperone function. The aim of this article is to provide a brief summary of the origin and concepts used in the intracellular chaperone field, to provide a backdrop for discussion of their possible roles outside the cell.

Protein misassembly: macromolecular crowding and molecular chaperones.

The generic tendency of proteins to misassemble into nonfunctional, and sometimes cytotoxic, structures poses a universal problem for all types of cell. This problem is exacerbated by the high total concentration of macromolecules found within most intracellular compartments but it is solved by the actions of molecular chaperones. This review discusses some of the basic evidence and key concepts relating to this conclusion.

Protein aggregation in crowded environments.

The generic tendency of proteins to aggregate into non-functional, and sometimes cytotoxic, structures poses a universal problem for all types of cell. This tendency is greatly exacerbated by the high total concentration of macromolecules found within most intracellular compartments, a phenomenon referred to as macromolecular crowding. This review discusses the quantitative effects of crowding on protein aggregation and the role of molecular chaperones in combating this problem.

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.

Chaperomics: in vivo GroEL function defined.

A recent proteome analysis of protein folding inside cells of Escherichia coli predicts that only 84 of the approximately 2400 cytosolic proteins expressed in minimal media depend absolutely on the GroEL/GroES chaperone system to avoid aggregation. These proteins are enriched in alpha/beta domains and 13 are essential for growth.