The Interaction of the Chaperonin Tailless Complex Polypeptide 1 (Tcp1) Ring Complex (Tric) with Ribosome-Bound Nascent Chains Examined Using Photo-Cross-Linking

McCallum, Christine; Do, Hung; Johnson, Arthur E.; Frydman, Judith

doi:10.1083/jcb.149.3.591

Cited by 82 publications

(76 citation statements)

References 54 publications

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“…RNAs encoding the Bcl-2 mutants were prepared from the corresponding pSPUTK-based plasmids using SP6 RNA polymerase as described (40). Translations of these RNAs were carried out in a rabbit reticulocyte lysate-based in vitro translation system with the ⑀ANB-Lys-tRNA Lys as described (41), except that the reactions contained 110 mM KOAc and were conducted for 50 min at 26°C.…”

Section: Methodsmentioning

confidence: 99%

Bcl-2 Homodimerization Involves Two Distinct Binding Surfaces, a Topographic Arrangement That Provides an Effective Mechanism for Bcl-2 to Capture Activated Bax

Zhi

Lapolla

Annis

et al. 2004

Journal of Biological Chemistry

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The homo-and heterodimerization of Bcl-2 family proteins is important for transduction and integration of apoptotic signals and control of the permeability of mitochondria and endoplasmic reticulum membranes. Here we mapped the interface of the Bcl-2 homodimer in a cell-free system using site-specific photocross-linking. Bcl-2 homodimer-specific photoadducts were detected from 11 of 17 sites studied. When modeled into the structure of Bcl-2 core, the interface is composed of two distinct surfaces: an acceptor surface that includes the hydrophobic groove made by helices 2 and 8 and the loop connecting helices 4 and 5 and a donor surface that is made by helices 1-4 and the loop connecting helices 2 and 3. The two binding surfaces are on separate faces of the three-dimensional structure, explaining the formation of Bcl-2 homodimers, homo-oligomers, and Bcl-2/ Bax hetero-oligomers. We show that in vitro the Bcl-2 dimer can still interact with activated Bax as a larger oligomer. However, formation of a Bax/Bcl-2 heterodimer is favored, since this interaction inhibits Bcl-2 homodimerization. Our data support a simple model mechanism by which Bcl-2 interacts with activated Bax during apoptosis in an effective manner to neutralize the proapoptotic activity of Bax.Bcl-2 family proteins are key regulators of apoptosis. These proteins share sequence homology in Bcl-2 homology (BH) 1 domains and function to promote or prevent apoptosis. Antiapoptotic proteins such as Bcl-2 and Bcl-x L show homology in four BH domains (BH1 to -4). Proapoptotic proteins can be grouped into "multidomain" and "BH3-only" subfamilies. Multidomain proapoptotic proteins such as Bax and Bak display homology in BH domains 1-3, whereas BH3-only proteins such as Bid and Bim are similar structurally to multidomain family members, but sequence similarity is limited to only the BH3 domain. The current model for how Bcl-2 family proteins regulate apoptosis involves three sequential processes: (i) BH3-only proteins are activated by various death signals; (ii) the active BH3-only proteins then either activate multidomain proapoptotic proteins or inhibit antiapoptotic proteins or both; and (iii) unless inhibited by antiapoptotic Bcl-2 proteins, activated multidomain proapoptotic proteins form oligomers in the mitochondrial outer membrane that release proapoptotic proteins such as cytochrome c and Smac/DIABLO from the mitochondrial intermembrane space. The released proteins trigger activation of the caspases and nucleases that eventually dismantle the cell (1-4).

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Section: Methodsmentioning

confidence: 99%

Bcl-2 Homodimerization Involves Two Distinct Binding Surfaces, a Topographic Arrangement That Provides an Effective Mechanism for Bcl-2 to Capture Activated Bax

Zhi

Lapolla

Annis

et al. 2004

Journal of Biological Chemistry

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“…Unlike the bacterial chaperonin GroEL, TRiC can bind co-translationally to nascent chains as they emerge from the ribosomes [23][24][25][26]. In the cell, binding to TRiC requires the assistance of upstream chaperones.…”

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

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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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“…For this set of experiments, CAD mRNA lacking a stop codon was prepared and translated in reticulocyte lysates (9,28,29). As shown in Fig.…”

Section: Atp-dependent Refolding Of Cad With Hsc70 Hsp40mentioning

confidence: 99%

Co-translational Folding of Caspase-activated DNase with Hsp70, Hsp40, and Inhibitor of Caspase-activated DNase

Sakahira¹,

Nagata²

2002

Journal of Biological Chemistry

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CAD (caspase-activated DNase) that causes chromosomal DNA fragmentation during apoptosis exists as a complex with ICAD (inhibitor of CAD) in proliferating cells. Here, we report that denatured CAD is functionally refolded with Hsc70-Hsp40 and ICAD. Hsc70-Hsp40 suppresses the aggregation of the denatured CAD, but cannot restore its enzymatic activity. In contrast, ICAD could not suppress the aggregation of CAD, but supported the CAD's renaturation with Hsc70-Hsp40, indicating that ICAD recognizes the quasi-native folding state of CAD that is conferred by Hsc70-Hsp40. Using an in vitro translation system, we then showed that during CAD translation, Hsc70-Hsp40 as well as ICAD bind to the nascent CAD polypeptide, while on ribosomes. These results indicate that ICAD together with Hsc70-Hsp40 assists the folding of CAD during its synthesis, and that the CAD⅐ICAD heterodimer is formed co-translationally.

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The Interaction of the Chaperonin Tailless Complex Polypeptide 1 (Tcp1) Ring Complex (Tric) with Ribosome-Bound Nascent Chains Examined Using Photo-Cross-Linking

Cited by 82 publications

References 54 publications

Bcl-2 Homodimerization Involves Two Distinct Binding Surfaces, a Topographic Arrangement That Provides an Effective Mechanism for Bcl-2 to Capture Activated Bax

Bcl-2 Homodimerization Involves Two Distinct Binding Surfaces, a Topographic Arrangement That Provides an Effective Mechanism for Bcl-2 to Capture Activated Bax

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

Co-translational Folding of Caspase-activated DNase with Hsp70, Hsp40, and Inhibitor of Caspase-activated DNase

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