A detailed understanding of how the ATPase cycle drives proteolysis of protein substrates has not yet been achieved for the ATP-dependent proteases. Thus, both systems are to a first approximation two-state systems, although, in the case of GroEL, anticooperative interplay between the two rings and asymmetric binding of GroES provide for at least one additional substate that is critical to the forward movement of the reaction cycle (see below). In both families of ATPases, large-scale conformational changes are dictated by the presence or absence of the γ phosphate of the bound adenine nucleotide. By contrast, the design of the ATPase domain of the chaperonins appears to be specific to chaperonins themselves (see, e.g., ref. All known ATP-dependent proteases belong to the Walker family of ATPases, a vast and functionally diverse collection of enzymes ( 12). In any case, there is no significant sequence similarity between these two types of ATPase rings. The functional similarities between the ATPase rings of the chaperonins and the ATP-dependent proteases may be an example of evolutionary convergence. In the case of the ring chaperones involved in proteolytic degradation, their action appears to involve recognition of specific proteins, destabilization of their structure, and translocation of unfolded polypeptide chains into associated proteolytic cylinders (see ref. In the case of chaperonins, their overall function is well established: namely, assisting proteins to fold to their native form. Chaperone rings serving as proteolytic assistants include the bacterial ClpA ( 6), ClpX ( 7), and HslU ( 8) and the eukaryotic 19S proteasome cap structure (regulatory particle), also known as PA700 (refs. Folding substrates leave such rings by retracing their original path of entry whereas proteolytic substrates appear to pass through the ring into a second, ATP-independent ring compartment containing proteolytic active sites.ĪTP-dependent chaperone rings have proven to be evolutionarily ubiquitous and include well studied protein-folding chaperonins, such as bacterial GroEL ( 3), the archaebacterial thermosome ( 4), and the eukaryotic CCT complex (ref. The cavity defines the substrate binding site, and the substrate can enter or exit this cavity by moving perpendicular to the plane of the ring. The ATPase subunits within these machines form symmetric or pseudosymmetric rings of 6–9 members, enclosing a central cavity ( Fig. These complexes, like many other protein machines, are driven by ATP, but their common physical feature is a ring structure. Independent studies of these two processes, however, have recently revealed their dependence in vivo on large and remarkably intricate molecular machines (refs. Because both processes are exergonic, it was long assumed that they occur through straightforward molecular mechanisms or simply spontaneously, in the case of folding. Here we review the structures and mechanisms of the two types of chaperone ring system.Īlmostallproteins proceed through a life cycle circumscribed by their folding and degradation. These divergent fates are at least partly governed by very different cooperating components that associate with the chaperone rings: that is, cochaperonin rings on one hand and proteolytic ring assemblies on the other. In the case of chaperonins, ATP enables a released protein to pursue the native state in a sequestered hydrophilic folding chamber, and, in the case of the proteases, the released polypeptide is translocated into a degradation chamber. For both folding and proteolytic complexes, ATP directs conformational changes in the chaperone rings that govern release of the bound polypeptide. At the step of recognition, chaperone rings recognize different motifs in their substrates, exposed hydrophobicity in the case of protein-folding chaperonins, and specific “tag” sequences in at least some cases of the proteolytic chaperones. Such restriction prevents outside interference that could lead to nonproductive fates of the substrate protein while it is present in non-native form, such as aggregation. Ring structures present an advantage to both processes, providing for compartmentalization of the substrate protein inside a central cavity in which multivalent, potentially cooperative interactions can take place between the substrate and a high local concentration of binding sites, while access of other proteins to the cavity is restricted sterically. *Department of Genetics and †Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT 06510 and §Department of Cell Biology, Harvard Medical School, Boston, MA 02115ĪBSTRACT Chaperone rings play a vital role in the opposing ATP-mediated processes of folding and degradation of many cellular proteins, but the mechanisms by which they assist these life and death actions are only beginning to be understood. ![]() Chaperone rings in protein folding and degradationĪ RTHUR L.
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