Molecular chaperones: physical and mechanistic properties.
Molecular chaperones can be broadly defined as proteins which interact with non-native states of other protein molecules. This activity is important in the folding of newly synthesized polypeptides and the assembly of multisubunit structures; the maintenance of proteins in unfolded states suitable for translocation across membranes; and the stabilization of inactive forms of proteins which are turned on by cellular signals; and the stabilization of proteins unfolded during cellular stress. The major chaperone classes are hsp60 (including TCP1), hsp70 and hsp90. All these proteins prevent the aggregation of unfolded proteins and the strength of interaction with their protein substrates is modified by the binding and hydrolysis of ATP. Hsp70 is a dimeric and ubiquitous protein which binds its substrates in an extended conformation through hydrophobic interactions. It binds to newly synthesized proteins and is required for protein transport. In its ATP-bound state it has a low protein affinity but when the nucleotide is hydrolysed to give the ADP state the affinity is increased. Hsp70 in E. coli (DnaK) is regulated by two co-proteins: DnaJ (of which there are homologues in eukaryotes) stimulates hydrolysis of ATP and GrpE promotes the dissociation of ADP to allow rebinding of ATP. Thus DnaJ promotes the association of substrate proteins and GrpE promotes dissociation. Hsp60 is a large, tetradecameric protein with a central cavity in which non-native protein structures are proposed to bind. It is essential for the folding of a huge spectrum of unrelated proteins and is present in all biological compartments except the ER. As in hsp70, the binding of ATP stimulates release of the substrate and its hydrolysis restores high binding affinity. It functions in conjunction with a co-protein, cpn10, which enhances its ability to eject proteins during the ATPase cycle. The enhancement of folding yields arises either from the prevention of irreversible aggregation or the ability to unfold misfolded structures and allow further attempts to arrive at the native state. Proteins of the hsp90 class are found associated with inactive or unstable substrate proteins within the cell, thus preventing their aggregation and/or permitting rapid activation.
Burston
S G
SG
Department of Biochemistry and Molecular Recognition Centre, University of Bristol, School of Medical Sciences, University Walk, U.K.
Clarke
A R
AR
D056404:Chaperonin Containing TCP-1; D018833:Chaperonins / Q000737:chemistry / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism; D018832:Molecular Chaperones / Q000737:chemistry* / Q000378:metabolism*; D017510:Protein Folding
D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D056404:Chaperonin Containing TCP-1; D018833:Chaperonins