The mechanistic target of rapamycin (mTOR) kinase forms two multi-protein signaling complexes, mTORC1 and mTORC2, which are master regulators of cell growth, metabolism, survival and autophagy. Two of the subunits of these complexes are mLST8 and Raptor, β-propeller proteins that stabilize the mTOR kinase and recruit substrates, respectively. Here we report that the eukaryotic chaperonin CCT plays a key role in mTORC assembly and signaling by folding both mLST8 and Raptor. A high resolution (4.0 Å) cryo-EM structure of the human mLST8-CCT intermediate isolated directly from cells shows mLST8 in a near-native state bound to CCT deep within the folding chamber between the two CCT rings, and interacting mainly with the disordered N- and C-termini of specific CCT subunits of both rings. These findings describe a unique function of CCT in mTORC assembly and a distinct binding site in CCT for mLST8, far from those found for similar β-propeller proteins.

Introduction: During the coronavirus disease 2019 (COVID-19) vaccination campaign, non-English-communicating individuals have faced inequities in access to resources for vaccine education and uptake. We characterized the language translation status of states' COVID-19 vaccine websites to inform discussion on the sufficiency of translated information and strategies for expanding the availability of multilingual vaccine information. Methods: We identified the primary COVID-19 vaccine website for all 50 states, the District of Columbia, and the federal government (“jurisdictions”) and determined the languages into which information about obtaining the vaccine (access) and vaccine safety and efficacy had been translated, as of October 2021. We compared these findings with data from the American Community Survey to determine how many individuals had these online resources available in their primary language. Results: Only 56% of jurisdictions provided professionally translated information about COVID-19 vaccine safety and efficacy, and only 50% provided professionally translated information about how to register for or obtain the COVID-19 vaccine, in at least one language. Consequently, ∼26 million Americans may not have accurate vaccine safety and efficacy information available, and ∼29 million Americans may not have vaccine access information available, from their jurisdiction in their primary language. Furthermore, translated information often was limited in scope and/or number of languages provided. Conclusion: Translation of COVID-19 vaccine information on state government websites currently is insufficient to meet the needs of non-English-communicating populations. This analysis can inform discussions about resource needs and operational considerations for adequate provision of multilingual, critical health information.

Cells respond to many hormones, neurotransmitters, bioactive peptides and sensory molecules through G protein signalling. The process begins with the binding of the signalling molecule to the extracellular face of a G‐protein‐coupled receptor (GPCR) that initiates binding of the G protein heterotrimer on the intracellular side of the receptor. This interaction causes exchange of GDP for GTP on the G protein α subunit, triggering a conformational change that dissociates the Gα‐GTP from Gβγ. These G protein subcomplexes then interact with effector enzymes and ion channels and elicit a cellular response to the signal. GPCRs constitute the largest class of transmembrane receptors, with 800 genes in the human genome. Consequently, G protein signalling contributes to almost all aspects of human physiology, and GPCRs are the single most common class of drug targets. Key Concepts G protein signalling contributes to almost all aspects of human physiology, including sensory perception, neuronal transmission and hormone secretion. Agonist binding to a G‐protein‐coupled receptor initiates an interaction with the G protein heterotrimer that triggers nucleotide exchange on the G protein α subunit (Gα). The binding of GTP to Gα causes its dissociation from the receptor and the G protein βγ dimer (Gβγ), allowing Gα‐GTP and Gβγ to interact with effector enzymes and ion channels. Effector enzymes and ion channels change the concentration of second messenger molecules or the membrane potential to elicit the cellular response to the agonist. The rate of GTP hydrolysis by Gα, which determines the duration of the G protein signal, is controlled by GTPase‐accelerating proteins called regulators of G protein signalling. To function, the G protein heterotrimer must be assembled from its individual subunits by molecular chaperones.

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The mechanistic target of rapamycin (mTOR) kinase forms two multi‐protein signaling complexes, mTORC1 and mTORC2, which are master regulators of cell growth, metabolism, survival and autophagy. Two of the subunits of these complexes are mLST8 and Raptor, β‐propeller proteins that stabilize the mTOR kinase and recruit substrates, respectively. Here we report that the eukaryotic chaperonin CCT plays a key role in mTORC assembly and signaling by folding both mLST8 and Raptor. A high resolution (4.0 Å) cryo‐EM structure of the human mLST8‐CCT intermediate isolated directly from cells shows mLST8 in a near‐native state bound to CCT deep within the folding chamber between the two CCT rings, and interacting mainly with the disordered N‐ and C‐termini of specific CCT subunits of both rings. These findings describe a unique function of CCT in mTORC assembly and a distinct binding site in CCT for mLST8, far from those found for similar β‐propeller proteins. Support or Funding Information This research was supported by the grant BFU2016‐75984 (AEI/FEDER, EU) and the Madrid Regional Government (grant S2013/MIT2807) to JMV as well as the US National Institutes of Health grant EY012287 to BMW and fellowships from the Brigham Young University Simmons Center for Cancer Research to WGL, NCT, TA and MD.