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Review
. 1999 Sep 28;96(20):11033-40.
doi: 10.1073/pnas.96.20.11033.

Chaperone rings in protein folding and degradation

A L Horwich  1 , E U Weber-Ban, D Finley
Affiliations
Review

Chaperone rings in protein folding and degradation

A L Horwich et al. Proc Natl Acad Sci U S A. .

Abstract

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. 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. 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. 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. For both folding and proteolytic complexes, ATP directs conformational changes in the chaperone rings that govern release of the bound polypeptide. 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. 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. Here we review the structures and mechanisms of the two types of chaperone ring system.

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Figures

Figure 1
Figure 1
Schematic illustration of the role of chaperone rings in ATP-dependent protein folding and unfolding/degradation in prokaryotic and eukaryotic cells. Protein folding chaperonins are illustrated in the upper portion of each “cell,” and proteolytic chaperones and the associated proteolytic cylinders are shown in the lower portion. In the case of the prokaryotic Clp components, the homohexameric ATPases, ClpA or ClpX, form coaxial associations with the termini of the double ring cylindrical serine protease, ClpP, delivering recognized substrates to it for degradation (see text). In the absence of association with ClpP, however, ClpA or ClpX can mediate disassembly of oligomeric substrate proteins, exemplified by ClpX-mediated disassembly of the MuA transposase tetramer. Note the two chaperonin classes in the eukaryotic cell (cytosolic and mitochondrial). In the case of the eukaryotic proteasome, the general pathways of ubiquitination to direct proteins for degradation by the proteasome are shown. Not shown is the presence of the proteasome in the nuclear compartment, where similar pathways of turnover appear to be operative.
Figure 2
Figure 2
Architecture of the eukaryotic proteasome and bacterial ClpAP chaperone–protease complexes and of the bacterial GroEL-GroES chaperonin pair. Side views from electron microscopy of the eukaryotic 26S proteasome (Left) and bacterial ClpAP (Center) showing the respective chaperone assemblies associated with the respective proteolytic cylinders (taken from ref. 11). The stoichiometries of the constitutent oligomeric rings are designated by subscripts; note that the eukaryotic proteasome is composed of seven distinct α subunits and seven distinct β subunits arranged 2-fold symmetrically to compose the four rings. Shown below are space-filling cutaway images of the proteolytic cylinders, derived from the crystal structures of Wang et al. (31) and Groll et al. (32), with active sites shown as red dots, as well as ribbon diagrams of their entryways, also taken from ref. . A space-filling view of the GroEL-GroES-ADP7 asymmetric chaperonin complex is shown (Upper Right), taken from Xu et al. (3), illustrating the differences between GroEL rings in the polypeptide-accepting and folding-active states. The open trans ring of the asymmetric complex exposes hydrophobic residues (shown in yellow) that can capture a non-native polypeptide. Subsequent GroES/ATP binding to the ring with polypeptide replaces this surface with a hydrophilic one (shown in blue), enlarges the cavity 2-fold in volume, and encapsulates the space in which a polypeptide, released from the hydrophobic binding sites, pursues folding in solitary confinement. Below, the rigid body movements of apical (red) and intermediate (green) domains of GroEL that occur on GroES binding are shown, taken from Xu et al. (3). The apical peptide binding surfaces of helices H and I (arrows), as well as an underlying segment, are removed from facing the central cavity to a position rotated upward 60° and twisted 90° clockwise (see text and ref. for details).
Figure 3
Figure 3
GroEL-GroES reaction cycle–rings alternate in formation of folding-active cis ternary complexes. Folding is triggered when ATP and GroES bind to the same (cis) ring as polypeptide, releasing it into the GroES-encapsulated, enlarged, and now hydrophilic cavity. This very stable complex is the longest-lived state of the chaperonin system in the presence of non-native polypeptide (63), and it is weakened and prepared for dissociation by hydrolysis in the cis ring, which allows entry of ATP and non-native polypeptide into the trans ring (30). These in turn accelerate the dissociation of the cis ligands, including polypeptide. GroES binds to the ATP/polypeptide-liganded trans ring, completing formation of a new cis complex on this ring. Thus, GroEL rings alternate back and forth as folding-active (see text for additional detail).
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References

    1. Baumeister W, Walz J, Zühl, Seemüller E. Cell. 1998;92:367–380. - PubMed
    1. Bukau B, Horwich A L. Cell. 1988;92:351–366. - PubMed
    1. Xu Z, Horwich A L, Sigler P B. Nature (London) 1997;388:741–750. - PubMed
    1. Ditzel L, Löwe J, Stock D, Stetter K-O, Huber H, Huber R, Steinbacher S. Cell. 1998;93:125–138. - PubMed
    1. Lewis V A, Hynes G M, Zheng D, Saibil H, Willison K. Nature (London) 1992;358:249–252. - PubMed

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