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(NAS Colloquium) Proteolytic Processing and Physiological Regulation (1999) / Chapter Skim
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Chaperone rings in protein folding and degradation
Pages 11033-11040

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From page 11033...
... The chaperone rings of the ATP-dependent proteases appear to play a preparative role, recognizing proteins slated for turnover and promoting their unfolding, actions that the proteolytic cylinders cannot by themselves carry out. Indeed, in the absence of the associating chaperone ring, proteolytic cylinders, such as bacterial ClpP or the eukaryotic 20S proteasome, degrade small peptides inefficiently a-nd are inactive on physiological protein substrates (see, e.g., refs.
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From page 11034...
... Protease-associated chaperone rings also exhibit axial cavities but, in contrast with those of chaperoning, these seem likely to be, in the active state, continuous channels through which recognized substrate proteins can be translocated into the central space of the associated proteolytic cylinder (11~. The diameter of such channels is somewhat uncertain, lacking crystallographic resolution so far, but recent cryoEM studies approximate the cavity in bacterial ClpA to 70-80 A at the widest point, narrowing down to a 10- to 20-A passageway at the end that interfaces with ClpP (6~.
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From page 11035...
... 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.
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From page 11036...
... If ubiquitin and substrate bind at multiple points to the lid and base, then ATP-mediated conformational change could exert a shearing force on the attached substrate protein that would act to unfold it. It seems that the lid structure would, at a minimum, allow retention of ubiquitinated proteins in proximity to the base apparatus, kinetically favoring interaction with it and the consequent ATP-dependent unfolding and translocation into the proteolytic cylinder.
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From page 11037...
... By contrast, complexes formed with ClpA hexamer at 23°C in ATP^yS were stable and "committed," such that they could only release RepA after exposure to ATP, discharging it as the DNA binding-competent monomer. In the case of chaperoning, it is clear that specific primary sequences in non-native substrate proteins are not involved with recognition but, rather, that structures with exposed hydrophobic surfaces, such as collapsed states that can bind in the central cavity of the chaperonin, are recognized (see ref.
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From page 11038...
... These studies indicate commitment of dimeric RepA substrate to dissociation into monomers in one round of interaction with the chaperone. Such committed behavior with respect to substrate protein differs considerably from that of chaperonins, which appear to eject substrate proteins after a timed period of folding in the cis chamber, regardless of whether substrate has reached the native state or not (see ref.
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From page 11039...
... Although the proteolytic system appears generally to be a committed one, it seems to have evolved a fail-safe mechanism or "editor" that prevents inappropriate commitment to turning over potentially active substrate proteins. The PA700 isopeptidase, an integral component of the mammalian l9S cap, enables removal of ubiquitin monomers from polyubiquitinated proteins, affording the chance to rescue those proteins that bear only short lengths of ubiquitin chains (ref.
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From page 11040...
... 11040 Colloquium Paper: Horwich et al.
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Key Terms

  • chaperone rings
  • proteolytic cylinders
  • substrate protein
  • atp binding
  • substrate proteins

  • chaperone ring
  • regulatory particle
  • ubiquitinated proteins
  • eukaryotic proteasome
  • native state

  • central cavity
  • apical domains
  • conformational change
  • associated proteolytic
  • nascent chain

  • conformational changes
  • proteasome cap
  • proteolytic chaperones
  • binding sites
  • ubiquitin chain

  • binding site
  • protein folding
  • axial cavities
  • cap structure
  • active sites

  • cis adp
  • medical institute
  • substrate polypeptide
  • proteolytic complexes
  • exposed hydrophobic


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