The 'sequential allosteric ring' mechanism in the eukaryotic chaperonin-assisted folding of actin and tubulin

Llorca, Óscar; Martín‐Benito, Jaime; Grantham, Julie; Ritco-Vonsovici, Monica; Willison, Keith R.; Carrascosa, José L.; Valpuesta, José M.

doi:10.1093/emboj/20.15.4065

Cited by 138 publications

(154 citation statements)

References 40 publications

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“…Syndapin regulates endocytosis and actin dynamics (59). Chaperonin containing tail-less complex polypeptide 1 is known to assist folding of actin and tubulin (60). Insulin receptor tyrosine kinase substrate p58/53 interacts with the ProSAP/Shank scaffolding proteins of the PSD (61); in addition to its function as a substrate of insulin receptor signaling this protein is also known to regulate cytosketelal dynamics (62).…”

Section: Discussionmentioning

confidence: 99%

Proteomics Analysis of Rat Brain Postsynaptic Density

Hornshaw

Schors

et al. 2004

Journal of Biological Chemistry

235

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The postsynaptic density contains multiple protein complexes that together relay the presynaptic neurotransmitter input to the activation of the postsynaptic neuron. In the present study we took two independent proteome approaches for the characterization of the protein complement of the postsynaptic density, namely 1) two-dimensional gel electrophoresis separation of proteins in conjunction with mass spectrometry to identify the tryptic peptides of the protein spots and 2) isolation of the trypsin-digested sample that was labeled with isotope-coded affinity tag, followed by liquid chromatography-tandem mass spectrometry for the partial separation and identification of the peptides, respectively. Functional grouping of the identified proteins indicates that the postsynaptic density is a structurally and functionally complex organelle that may be involved in a broad range of synaptic activities. These proteins include the receptors and ion channels for glutamate neurotransmission, proteins for maintenance and modulation of synaptic architecture, sorting and trafficking of membrane proteins, generation of anaerobic energy, scaffolding and signaling, local protein synthesis, and correct protein folding and breakdown of synaptic proteins. Together, these results imply that the postsynaptic density may have the ability to function (semi-) autonomously and may direct various cellular functions in order to integrate synaptic physiology.The majority of excitatory neurotransmission in the brain occurs via glutamatergic synapses. In the presynaptic element of the synapse, specialized secretion machinery determines the activity-dependent membrane fusion of glutamate-containing vesicles and the release of transmitter into the synaptic cleft. In the postsynaptic element, glutamate receptors and downstream signal transduction are organized by the protein assembly of the postsynaptic density (PSD). 1 Both the presynaptic release machinery and the PSD are electron-dense assemblies (1, 2), in which proteins are thought to be organized into distinct functional complexes (3-5) that may be dynamically regulated by neuronal activity (6 -8). The modulation of this molecular architecture of the synapse is at the basis of synaptic plasticity (6 -8), and aberrations thereof may underlie neuronal disorders.In view of the importance of the PSD in glutamatergic neurotransmission and its involvement in neuroplasticity, considerable efforts have been made to identify its protein constituents as a prelude to understand the molecular basis of PSD functioning. In the past several years, yeast two-hybrid technology has been extensively used to characterize proteins that interact with the glutamate receptors and may constitute core elements of the PSD involved in the regulation of receptor trafficking and signaling (reviewed in Refs. 9 -11). Based largely on these studies a protein-protein interaction map of the PSD has emerged. In brief, the model posits that the postsynaptic receptor complexes are localized by scaffolding proteins such as the s...

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Section: Discussionmentioning

confidence: 99%

Proteomics Analysis of Rat Brain Postsynaptic Density

Hornshaw

Schors

et al. 2004

Journal of Biological Chemistry

235

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“…Amino acid residues within the ring make contacts with the unfolded protein and decrease the activation energy required to form the three-dimensional structure of the native protein [73]. Each CCT subunit binds ATP and uses the energy of ATP hydrolysis to drive the folding process [74,75]. Actin and tubulin are major cellular proteins that require CCT to fold, but other substrates have been described.…”

Section: Over-turning the Paradigm -Phlp1 As An Essential Co-chaperonmentioning

confidence: 99%

Function of phosducin-like proteins in G protein signaling and chaperone-assisted protein folding

Willardson

Howlett

2007

Cellular Signalling

100

101

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Members of the phosducin gene family were initially proposed to act as down-regulators of G protein signaling by binding G protein βγ dimers (Gβγ) and inhibiting their ability to interact with G protein α subunits (Gα) and effectors. However, recent findings have overturned this hypothesis by showing that most members of the phosducin family act as cochaperones with the cytosolic chaperonin complex (CCT) to assist in the folding of a variety of proteins from their nascent polypeptides. In fact rather than inhibiting G protein pathways, phosducin-like protein 1 (PhLP1) has been shown to be essential for G protein signaling by catalyzing the folding and assembly of the Gβγ dimer. PhLP2 and PhLP3 have no role in G protein signaling, but they appear to assist in the folding of proteins essential in regulating cell cycle progression as well as actin and tubulin. Phosducin itself is the only family member that does not participate with CCT in protein folding, but it is believed to have a specific role in visual signal transduction to chaperone Gβγ subunits as they translocate to and from the outer and inner segments of photoreceptor cells during light-adaptation.

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“…An intraring subunit arrangement proposed from analysis of spontaneously dissociated TRiC complexes remains untested (24). Previous cryo-EM studies of TRiC achieved only up to ∼15-Å resolution with imposed 8-fold symmetry (13,25,26), inadequate to resolve the asymmetry between the eight structurally similar subunits. Here we present a high-resolution cryo-EM structure of mammalian TRiC, derived without imposing any symmetry among the eight subunits.…”

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confidence: 99%

4.0-Å resolution cryo-EM structure of the mammalian chaperonin TRiC/CCT reveals its unique subunit arrangement

Yao

Baker

Jakana

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

157

147

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The essential double-ring eukaryotic chaperonin TRiC/CCT (TCP1-ring complex or chaperonin containing TCP1) assists the folding of ∼5-10% of the cellular proteome. Many TRiC substrates cannot be folded by other chaperonins from prokaryotes or archaea. These unique folding properties are likely linked to TRiC's unique heterooligomeric subunit organization, whereby each ring consists of eight different paralogous subunits in an arrangement that remains uncertain. Using single particle cryo-EM without imposing symmetry, we determined the mammalian TRiC structure at 4.7-Å resolution. This revealed the existence of a 2-fold axis between its two rings resulting in two homotypic subunit interactions across the rings. A subsequent 2-fold symmetrized map yielded a 4.0-Å resolution structure that evinces the densities of a large fraction of side chains, loops, and insertions. These features permitted unambiguous identification of all eight individual subunits, despite their sequence similarity. Independent biochemical near-neighbor analysis supports our cryo-EM derived TRiC subunit arrangement. We obtained a Cα backbone model for each subunit from an initial homology model refined against the cryo-EM density. A subsequently optimized atomic model for a subunit showed ∼95% of the main chain dihedral angles in the allowable regions of the Ramachandran plot. The determination of the TRiC subunit arrangement opens the way to understand its unique function and mechanism. In particular, an unevenly distributed positively charged wall lining the closed folding chamber of TRiC differs strikingly from that of prokaryotic and archaeal chaperonins. These interior surface chemical properties likely play an important role in TRiC's cellular substrate specificity.asymmetric reconstruction | atomic model | subunit structure

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The 'sequential allosteric ring' mechanism in the eukaryotic chaperonin-assisted folding of actin and tubulin

Cited by 138 publications

References 40 publications

Proteomics Analysis of Rat Brain Postsynaptic Density

Proteomics Analysis of Rat Brain Postsynaptic Density

Function of phosducin-like proteins in G protein signaling and chaperone-assisted protein folding

4.0-Å resolution cryo-EM structure of the mammalian chaperonin TRiC/CCT reveals its unique subunit arrangement

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