First glimpses of a chaperonin-bound folding intermediate

Swain, Joanna F.; Gierasch, Lila M.

doi:10.1073/pnas.0506510102

Cited by 6 publications

(5 citation statements)

References 21 publications

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“…Passive unfolding is probably caused by the high density of hydrophobic surface on the inner apical face of an open GroEL ring, where non-native proteins like Rubisco make multiple, simultaneous binding contacts 49 . The high local concentration of hydrophobic surface on the interior of an open GroEL ring probably catalyzes the rearrangement and partial unfolding of the protein, perhaps in a manner analogous to surface-mediated denaturation 50,51 . The observation that the trans ring of an ADP bullet is less capable of passive unfolding suggests that either a trans ring cannot engage a substrate protein across multiple apical domains in the same way that an apoGroEL ring can, or that the trans ring is not capable of dynamically adjusting its structure in response to substrate-protein binding in the same manner as the less constrained apoGroEL ring 52 .…”

Section: Discussionmentioning

confidence: 99%

GroEL stimulates protein folding through forced unfolding

Lin

Madan

Rye

2008

Nat Struct Mol Biol

146

208

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Many proteins cannot fold without the assistance of chaperonin machines like GroEL and GroES. The nature of this assistance, however, remains poorly understood. Here we demonstrate that unfolding of a substrate protein by GroEL enhances protein folding. We first show that capture of a protein on the open ring of a GroEL-ADP-GroES complex, GroEL's physiological acceptor state for non-native proteins in vivo, leaves the substrate protein in an unexpectedly compact state. Subsequent binding of ATP to the same GroEL ring causes rapid, forced unfolding of the substrate protein. Notably, the fraction of the substrate protein that commits to the native state following GroES binding and protein release into the GroEL-GroES cavity is proportional to the extent of substrate-protein unfolding. Forced protein unfolding is thus a central component of the multilayered stimulatory mechanism used by GroEL to drive protein folding.

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Section: Discussionmentioning

confidence: 99%

GroEL stimulates protein folding through forced unfolding

Lin

Madan

Rye

2008

Nat Struct Mol Biol

146

208

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“…Subsequent on-ring rearrangements of a folding intermediate (e.g., Lin and Rye, 2004) would then result in highly stable and simultaneous binding of several regions of a folding intermediate to different segments of a GroEL ring. The overall effect might be similar to surface-dependent protein denaturation (Sharp et al, 2002;Swain and Gierasch, 2005).…”

Section: Evidence For Catalytic Unfoldingmentioning

confidence: 99%

GroEL-Mediated Protein Folding: Making the Impossible, Possible

Lin

Rye

2006

Critical Reviews in Biochemistry and Molecular Biology

158

135

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Protein folding is a spontaneous process that is essential for life, yet the concentrated and complex interior of a cell is an inherently hostile environment for the efficient folding of many proteins. Some proteins-constrained by sequence, topology, size, and function-simply cannot fold by themselves and are instead prone to misfolding and aggregation. This problem is so deeply entrenched that a specialized family of proteins, known as molecular chaperones, evolved to assist in protein folding. Here we examine one essential class of molecular chaperones, the large, oligomeric, and energy utilizing chaperonins or Hsp60s. The bacterial chaperonin GroEL, along with its co-chaperonin GroES, is probably the best-studied example of this family of proteinfolding machine. In this review, we examine some of the general properties of proteins that do not fold well in the absence of GroEL and then consider how folding of these proteins is enhanced by GroEL and GroES. Recent experimental and theoretical studies suggest that chaperonins like GroEL and GroES employ a combination of protein isolation, unfolding, and conformational restriction to drive protein folding under conditions where it is otherwise not possible.

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“…Chaperonins mediate folding by undergoing a conformational cycle driven by ATP binding and hydrolysis. Although it is clear that the ring-shaped architecture is essential for folding, the exact mechanism by which chaperonins promote folding of a bound substrate remains to be established (Swain and Gierasch, 2005).…”

Section: Introductionmentioning

confidence: 99%

Identification of the TRiC/CCT Substrate Binding Sites Uncovers the Function of Subunit Diversity in Eukaryotic Chaperonins

et al. 2006

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The ring-shaped hetero-oligomeric chaperonin TRiC/CCT uses ATP to fold a diverse subset of eukaryotic proteins. To define the basis of TRiC/CCT substrate recognition, we mapped the chaperonin interactions with the VHL tumor suppressor. VHL has two well-defined TRiC binding determinants. Each determinant contacts a specific subset of chaperonin subunits, indicating that TRiC paralogs exhibit distinct but overlapping specificities. The substrate binding site in these subunits localizes to a helical region in the apical domains that is structurally equivalent to that of bacterial chaperonins. Transferring the distal portion of helix 11 between TRiC subunits suffices to transfer specificity for a given substrate motif. We conclude that the architecture of the substrate binding domain is evolutionarily conserved among eukaryotic and bacterial chaperonins. The unique combination of specificity and plasticity in TRiC substrate binding may diversify the range of motifs recognized by this chaperonin and contribute to its unique ability to fold eukaryotic proteins.

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First glimpses of a chaperonin-bound folding intermediate

Cited by 6 publications

References 21 publications

GroEL stimulates protein folding through forced unfolding

GroEL stimulates protein folding through forced unfolding

GroEL-Mediated Protein Folding: Making the Impossible, Possible

Identification of the TRiC/CCT Substrate Binding Sites Uncovers the Function of Subunit Diversity in Eukaryotic Chaperonins

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