The Cytosolic Class II Chaperonin CCT Recognizes Delineated Hydrophobic Sequences in Its Target Proteins

Rommelaere, Heidi; Neve, Myriam De; Melki, Ronald; Vandekerckhove, Joël; Ampè, Christophe

doi:10.1021/bi9815905

Cited by 61 publications

(87 citation statements)

References 55 publications

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“…Thus, like the situation in vitro, at least some pVHL interacts with CCT in vivo. Some polypeptides that fold via a CCT-mediated pathway (e.g., tubulins and actins) contain particular subdomains that display an affinity for CCT (6,19,49,50). Relevant to the present study, a 55-amino-acid region (residues 100 to 155) of pVHL has been shown to be necessary and sufficient for binding to CCT (9).…”

Section: Resultssupporting

confidence: 56%

Diverse Effects of Mutations in Exon II of the von Hippel-Lindau (VHL) Tumor Suppressor Gene on the Interaction of pVHL with the Cytosolic Chaperonin and pVHL-Dependent Ubiquitin Ligase Activity

Hansen

Ohh

Moslehi

et al. 2002

Molecular and Cellular Biology

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We examined the biogenesis of the von Hippel-Lindau (VHL) tumor suppressor protein (pVHL) in vitro and in vivo. pVHL formed a complex with the cytosolic chaperonin containing TCP-1 (CCT or TRiC) en route to assembly with elongin B/C and the subsequent formation of the VCB-Cul2 ubiquitin ligase. Blocking the interaction of pVHL with elongin B/C resulted in accumulation of pVHL within the CCT complex. pVHL present in purified VHL-CCT complexes, when added to rabbit reticulocyte lysate, proceeded to form VCB and VCB-Cul2. Thus, CCT likely functions, at least in part, by retaining VHL chains pending the availability of elongin B/C for final folding and/or assembly. Tumor-associated mutations within exon II of the VHL syndrome had diverse effects upon the stability and/or function of pVHL-containing complexes. First, a pVHL mutant lacking the entire region encoded by exon II did not bind to CCT and yet could still assemble into complexes with elongin B/C and elongin B/C-Cul2. Second, a number of tumor-derived missense mutations in exon II did not decrease CCT binding, and most had no detectable effect upon VCB-Cul2 assembly. Many exon II mutants, however, were found to be defective in the binding to and subsequent ubiquitination of hypoxia-inducible factor 1␣ (HIF-1␣), a substrate of the VCB-Cul2 ubiquitin ligase. We conclude that the selection pressure to mutate VHL exon II during tumorigenesis does not relate to loss of CCT binding but may reflect quantitative or qualitative defects in HIF binding and/or in pVHL-dependent ubiquitin ligase activity.

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Section: Resultssupporting

confidence: 56%

Diverse Effects of Mutations in Exon II of the von Hippel-Lindau (VHL) Tumor Suppressor Gene on the Interaction of pVHL with the Cytosolic Chaperonin and pVHL-Dependent Ubiquitin Ligase Activity

Hansen

Ohh

Moslehi

et al. 2002

Molecular and Cellular Biology

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“…However, the search for TRiC-recognition determinants in substrate proteins has yielded conflicting data. Studies using actin indicate several possibilities, ranging from polar and charged sequences surface-exposed on the native protein [33] to delineated, hydrophobic sequences [34]. Recognition of native, surface-exposed, charged elements is novel for a molecular chaperone and raises questions of how binding interactions might be disrupted permanently to release the folded substrate and how TRiC might discriminate between native and non-native states.…”

Section: Tric-substrate Interactionsmentioning

confidence: 99%

Mechanism of the eukaryotic chaperonin: protein folding in the chamber of secrets

Spiess

Meyer

Reißmann

et al. 2004

Trends in Cell Biology

342

327

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Chaperonins are key components of the cellular chaperone machinery. These large, cylindrical complexes contain a central cavity that binds to unfolded polypeptides and sequesters them from the cellular environment. Substrate folding then occurs in this central cavity in an ATP-dependent manner. The eukaryotic chaperonin TCP-1 ring complex (TRiC, also called CCT) is indispensable for cell survival because the folding of an essential subset of cytosolic proteins requires TRiC, and this function cannot be substituted by other chaperones. This specificity indicates that TRiC has evolved structural and mechanistic features that distinguish it from other chaperones. Although knowledge of this unique complex is in its infancy, we review recent advances that open the way to understanding the secrets of its folding chamber.Protein misfolding has been implicated in several human diseases that have both systemic and neurological implications, including 'conformational diseases' such as Huntington's and Parkinson's that are characterized by the accumulation of toxic protein aggregates [1]. Although small proteins with simple chain topologies can fold spontaneously, the vast majority of cellular proteins is unable to reach its native state without the assistance of elaborate cellular machinery composed of proteins known as molecular chaperones (for review, see Refs [1-4]). A complete understanding of chaperone-assisted protein folding in the cell would be an intellectual tour de force that might, eventually, lead to effective treatments for these diseases.In the cell, protein folding faces additional challenges compared with the refolding of proteins in solution [1,2,4]. For example, in vivo, the linear polypeptide chain emerges vectorially into the cytosol during synthesis on ribosomes. Because the information for the native state is encoded by the entire amino acid sequence, the nascent polypeptide chain is unable to fold stably until fully synthesized, but it exposes hydrophobic sequences into the crowded cellular milieu [4]. Details of how newly translated proteins navigate toward a final, fully functional, folded structure in vivo are not entirely understood, but it is clear that exposed hydrophobic surfaces can contribute to misfolding and aggregation. Accordingly, all cellular compartments contain many structurally and functionally distinct classes of chaperones that vary in size and complexity, ranging from those that bind only to misfolded polypeptides and prevent their aggregation to those that recognize specific classes of proteins and facilitate their folding to the native state in an energy-dependent manner [1][2][3]. In cells, these different classes of chaperones work together to form elaborate, cooperative networks that ensure the correct folding of newly translated proteins; they also ensure that potentially damaging misfolded polypeptides are cleared from the cell [5].

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“…However, no sequence homology between the p4 and p6 proteins can be seen except for their unusually high proline content. The core TRiC binding domain of ␤-tubulin was defined through mutagenesis and proteolytic analyses; it spans amino acids 150 to 350 and contains many proline and hydrophobic residues (6,40). There are no conserved sequences among the core domains of ␤-tubulin, VHL (10), and ␤-actin (20).…”

Section: Vol 75 2001mentioning

confidence: 99%

Type D Retrovirus Gag Polyprotein Interacts with the Cytosolic Chaperonin TRiC

Choi

Park

Chung

et al. 2001

J Virol

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The carboxy terminus-encoding portion of the gag gene of Mason-Pfizer monkey virus (M-PMV), the prototype immunosuppressive primate type D retrovirus, encodes a 36-amino-acid, proline-rich protein domain that, in the mature virion, becomes the p4 capsid protein. The p4 domain has no known role in M-PMV replication. We found that two mutants with premature termination codons that remove half or all of the p4 domain produced lower levels of stable Gag protein and of self-assembled capsids. Interestingly, yeast twohybrid screening revealed that p4 specifically interacted with TCP-1␥, a subunit of the chaperonin TRiC (TCP-1 ring complex). TRiC is a cytosolic chaperonin that is known to be involved in both folding and subunit assembly of a variety of cellular proteins. TCP-1␥ also associated with high specificity with the M-PMV pp24/16-p12 domain and human immunodeficiency virus p6. Moreover, in cells, Gag polyprotein associated with the TRiC chaperonin complex and this association depended on ATP hydrolysis. In the p4 truncation mutants, the Gag-TRiC association was significantly reduced. These results strongly suggest that cytosolic chaperonin TRiC is involved in Gag folding and/or capsid assembly. We propose that TRiC associates transiently with nascent M-PMV Gag molecules to assist in their folding. Consequently, properly folded Gag molecules carry out the intermolecular interactions involved in self-assembly of the immature capsid.

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The Cytosolic Class II Chaperonin CCT Recognizes Delineated Hydrophobic Sequences in Its Target Proteins

Cited by 61 publications

References 55 publications

Diverse Effects of Mutations in Exon II of the von Hippel-Lindau (VHL) Tumor Suppressor Gene on the Interaction of pVHL with the Cytosolic Chaperonin and pVHL-Dependent Ubiquitin Ligase Activity

Diverse Effects of Mutations in Exon II of the von Hippel-Lindau (VHL) Tumor Suppressor Gene on the Interaction of pVHL with the Cytosolic Chaperonin and pVHL-Dependent Ubiquitin Ligase Activity

Mechanism of the eukaryotic chaperonin: protein folding in the chamber of secrets

Type D Retrovirus Gag Polyprotein Interacts with the Cytosolic Chaperonin TRiC

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