Structural and functional analysis of the role of the chaperonin CCT in mTOR complex assembly

Cuéllar, Jorge; Ludlam, W. Grant; Tensmeyer, Nicole C.; Aoba, Takuma; Dhavale, Madhura; Santiago, César; Bueno-Carrasco, M. Teresa; Mann, Michael J.; Plimpton, Rebecca L.; Makaju, Aman; Franklin, Sarah; Willardson, Barry M.; Valpuesta, José M.

doi:10.1038/s41467-019-10781-1

Cited by 61 publications

(88 citation statements)

References 70 publications

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“…For example, CCT6B , a subunit of the chaperonin containing TCP1 (CCT) complex (also known as TRiC), is a 5′TOP mRNA, and several other CCT mRNAs only slightly missed our stringent criteria for defining 5′TOP mRNAs (e.g., CCT7 has a TOPscore of 8.4, was relatively translationally repressed 1.4-fold by Torin2 in wild-type, and was not relatively translationally repressed by Torin2 in larp1 ). The CCT complex promotes assembly of many proteins, including RAPTOR and LST8 ( Cuéllar et al, 2019 ), but is most famously associated with assembly of actin and tubulin subunits ( Balchin et al, 2018 ; Dekker et al, 2008 ; Yam et al, 2008 ). In mammals, TOR regulates CCT complex function by promoting phosphorylation of the CCT complex ( Abe et al, 2009 ), indicating that metabolic regulation of CCT complex activity by TOR may occur through multiple signal transduction pathways in different eukaryotic lineages.…”

Section: Discussionmentioning

confidence: 99%

Parallel global profiling of plant TOR dynamics reveals a conserved role for LARP1 in translation

Scarpin

Leiboff

Brunkard

2020

eLife

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TARGET OF RAPAMYCIN (TOR) is a protein kinase that coordinates eukaryotic metabolism. In mammals, TOR specifically promotes translation of ribosomal protein mRNAs when amino acids are available to support protein synthesis. The mechanisms controlling translation downstream from TOR remain contested, however, and are largely unexplored in plants. To define these mechanisms in plants, we globally profiled the plant TOR-regulated transcriptome, translatome, proteome, and phosphoproteome. We found that TOR regulates ribosome biogenesis in plants at multiple levels, but through mechanisms that do not directly depend on 5′ oligopyrimidine tract motifs (5′TOPs) found in mammalian ribosomal protein mRNAs. We then show that the TOR-LARP1-5′TOP signaling axis is conserved in plants and regulates expression of a core set of eukaryotic 5′TOP mRNAs, as well as new, plant-specific 5′TOP mRNAs. Our study illuminates ancestral roles of the TOR-LARP1-5′TOP metabolic regulatory network and provides evolutionary context for ongoing debates about the molecular function of LARP1.

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Section: Discussionmentioning

confidence: 99%

Parallel global profiling of plant TOR dynamics reveals a conserved role for LARP1 in translation

Scarpin

Leiboff

Brunkard

2020

eLife

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“…Therefore, the control of the activity of the PIKKs by their respective regulatory proteins might involve an allosteric mechanism mediated by binding to the N-HEAT domain, which can also serve as a platform for binding of specific proteins. domains, an interaction which is required for proper folding and mTORC1 assembly [124]. This interaction was not detected for mTOR, Rictor or mSin1.…”

Section: Beyond Cell Growth: Tor As a Pikkmentioning

confidence: 92%

“…Beyond mTOR, proper folding of the other mTORC1 subunits is also required. Recently, it has been shown that both mLst8 and Raptor bind to the chaperonin CCT via their β-propeller/WD40 domains, an interaction which is required for proper folding and mTORC1 assembly [124]. This interaction was not detected for mTOR, Rictor or mSin1.…”

Section: Beyond Cell Growth: Tor As a Pikkmentioning

confidence: 99%

Structural Insights into TOR Signaling

Tafur

Kefauver

Loewith

2020

Genes

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The Target of Rapamycin (TOR) is a highly conserved serine/threonine protein kinase that performs essential roles in the control of cellular growth and metabolism. TOR acts in two distinct multiprotein complexes, TORC1 and TORC2 (mTORC1 and mTORC2 in humans), which maintain different aspects of cellular homeostasis and orchestrate the cellular responses to diverse environmental challenges. Interest in understanding TOR signaling is further motivated by observations that link aberrant TOR signaling to a variety of diseases, ranging from epilepsy to cancer. In the last few years, driven in large part by recent advances in cryo-electron microscopy, there has been an explosion of available structures of (m)TORC1 and its regulators, as well as several (m)TORC2 structures, derived from both yeast and mammals. In this review, we highlight and summarize the main findings from these reports and discuss both the fascinating and unexpected molecular biology revealed and how this knowledge will potentially contribute to new therapeutic strategies to manipulate signaling through these clinically relevant pathways.

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“…Importantly, depleting CCT subunits in an autophagydeficient background did not further increase the aggregation of mutant huntingtin or the aggregation of another polyglutaminecontaining protein ataxin 3 (Pavel et al, 2016). Furthermore, the CCT oligomer is involved in folding components of the mTORC complex, thus affecting mTORC assembly (Cuellar et al, 2019). Therefore, loss of CCT oligomer could influence several cellular processes including autophagy via mTORCmediated pathways.…”

Section: Potential Mechanisms Of Actionmentioning

confidence: 99%

The Molecular Chaperone CCT/TRiC: An Essential Component of Proteostasis and a Potential Modulator of Protein Aggregation

Grantham

2020

Front. Genet.

102

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Chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC) is an essential eukaryotic molecular chaperone. It is a multi-subunit oligomer of two rings of eight individual protein subunits. When assembled, each of the eight CCT subunits occupies a specific position within each chaperonin ring. Thus a geometrically defined binding interface is formed from the divergent sequences within the CCT subunit substrate binding domains. CCT is required for the folding of the abundant cytoskeletal proteins actin and tubulin, which in turn form assemblies of microfilaments and microtubules. CCT is also involved in the folding of some additional protein substrates and some CCT subunits have been shown to have functions when monomeric. Since observations were made in worms over a decade ago using an RNAi screen, which connected CCT subunits to the aggregation of polyglutamine tracts, a role for CCT as a potential modulator of protein aggregation has started to emerge. Here there will be a focus on how mechanistically CCT may be able to achieve this and if this potential function of CCT provides any insights and directions for developing future treatments for protein aggregation driven neurodegenerative diseases generally, many of which are associated with aging.

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Structural and functional analysis of the role of the chaperonin CCT in mTOR complex assembly

Cited by 61 publications

References 70 publications

Parallel global profiling of plant TOR dynamics reveals a conserved role for LARP1 in translation

Parallel global profiling of plant TOR dynamics reveals a conserved role for LARP1 in translation

Structural Insights into TOR Signaling

The Molecular Chaperone CCT/TRiC: An Essential Component of Proteostasis and a Potential Modulator of Protein Aggregation

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