Regulation of the Target of Rapamycin and Other Phosphatidylinositol 3-Kinase-Related Kinases by  Membrane Targeting

Cicco, Maristella De; Rahim, Munirah S. Abd; Dames, Sonja A.

doi:10.3390/membranes5040553

Cited by 14 publications

(13 citation statements)

References 150 publications

(277 reference statements)

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“…The mammalian PIKK family constitutes of six proteins, namely: mammalian target of rapamycin (mTOR), ataxia-telangiectasia mutated (ATM), ATR, DNA-dependent protein kinase (DNA-PK), suppressor of morphogenesis in genitalia-1 (SMG-1), and transformation/transcription domain-associated protein (TRRAP). Unlike canonical PI3 kinases, the PIKKs lack lipid phosphorylation activity and function as protein kinases instead [10] .…”

Section: Introductionmentioning

confidence: 99%

ATR-mediated regulation of nuclear and cellular plasticity

2016

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ATR (Ataxia Telangiectasia and Rad3-related) is a member of the Phosphatidylinositol 3-kinase-related kinases (PIKKs) family, amongst six other vertebrate proteins known so far. ATR is indispensable for cell survival and its essential role is in sensing DNA damage and initiating appropriate repair responses. In this review we highlight emerging and recent observations connecting ATR to alternative roles in controlling the nuclear envelope, nucleolus, centrosome and other organelles in response to both internal and external stress conditions. We propose that ATR functions control cell plasticity by sensing structural deformations of different cellular components, including DNA and initiating appropriate repair responses, most of which are yet to be understood completely.

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Section: Introductionmentioning

confidence: 99%

ATR-mediated regulation of nuclear and cellular plasticity

2016

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“…It has been proposed that targeted membrane localization allows spatial separation of individual signaling branches of large signaling networks, thereby potentially improving the reliability of biochemical signaling processes (19). Because PIKKs generally participate in a multitude of signaling pathways in response to ionizing radiation and other stress factors or metabolic signals (2,5,7,16,20,21), their localization may also determine the specific signaling output (22). ATM has been found to localize and function not only in the nucleus but also in the cytoplasm (12).…”

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confidence: 99%

NMR– and MD simulation–based structural characterization of the membrane-associating FATC domain of ataxia telangiectasia mutated

Rahim

Cherniavskyi

Tieleman

et al. 2019

Journal of Biological Chemistry

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Edited by Wolfgang Peti The Ser/Thr protein kinase ataxia telangiectasia mutated (ATM) plays an important role in the DNA damage response, signaling in response to redox signals, the control of metabolic processes, and mitochondrial homeostasis. ATM localizes to the nucleus and at the plasma membrane, mitochondria, peroxisomes, and other cytoplasmic vesicular structures. It has been shown that the C-terminal FATC domain of human ATM (hAT-Mfatc) can interact with a range of membrane mimetics and may thereby act as a membrane-anchoring unit. Here, NMR structural and 15 N relaxation data, NMR data using spin-labeled micelles, and MD simulations of micelle-associated hATMfatc revealed that it binds the micelle by a dynamic assembly of three helices with many residues of hATMfatc located in the headgroup region. We observed that none of the three helices penetrates the micelle deeply or makes significant tertiary contacts to the other helices. NMR-monitored interaction experiments with hATMfatc variants in which two conserved aromatic residues (Phe 3049 and Trp 3052) were either individually or both replaced by alanine disclosed that the double substitution does not abrogate the interaction with micelles and bicelles at the high concentrations at which these aggregates are typically used, but impairs interactions with small unilamellar vesicles, usually used at much lower lipid concentrations and considered a better mimetic for natural membranes. We conclude that the observed dynamic structure of micelle-associated hATMfatc may enable it to interact with differently composed membranes or membrane-associated interaction partners and thereby regulate ATM's kinase activity. Moreover, the FATC domain of ATM may function as a membrane-anchoring unit for other biomolecules. Ataxia telangiectasia mutated (ATM) 4 belongs to the family of phosphatidylinositol 3-kinase-related kinases (PIKKs) that phosphorylate Ser/Thr residues of proteins regulating processes such as DNA repair, cell cycle progression, cellular senescence, apoptosis, and metabolic processes (1-4). Recently, it was found out that PIKKs also play a role in signaling in response to virus infections and during inflammation (5, 6). The function of ATM and of the related mammalian/mechanistic target of rapamycin (mTOR), a central controller of cell growth and metabolism in all eukaryotes that also has links to DNA repair signaling (7, 8), has further been related to redox signaling (9-12). Whereas the mTOR pathway negatively controls ATM (13), ATM inactivates mTORC1 in response to reactive oxygen species to induce autophagy (12), based on additional data, specifically that of peroxisomes (14). ATM also down-regulates mTORC1 under hypoxic conditions (11). Other studies indicate that ATM plays direct roles in modulating mitochondrial homeostasis (15). Activation of ATM by oxidation and other factors has been reviewed (16). Inactivation of ATM leads to ataxia-telangiectasia (A-T) disease and more generally plays a role in neuronal development and neurodegeneration (17)...

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“…TOR has been detected at different cellular membranes and in the nucleus. Based on these observations it has been suggested that the localization of TOR depends on the composition of the TOR complexes as well as on the cell type and signaling state and is mediated by an extensive network of protein‐protein and protein‐lipid interactions . The solution structure of the oxidized FATC domain of yeast TOR1 [residues 2438–2479, y1fatc, Fig.…”

Section: Introductionmentioning

confidence: 99%

“…This can be explained by the significantly lower sample concentration of SUVs compared to micelles and bicelles as well as their larger radius and thus lower membrane curvature. The FATC domain is shared by all members of the family of phosphatidylinositol‐3 kinase‐related kinases (PIKKs), which control cellular signaling pathways in response to stress and nutrients . All have been shown to interact with membrane mimetics albeit with differences in the preferences for specific membrane properties …”

Section: Introductionmentioning

confidence: 99%

Target of rapamycin FATC domain as a general membrane anchor: The FKBP‐12 like domain of FKBP38 as a case study

2017

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Increased efforts have been undertaken to better understand the formation of signaling complexes at cellular membranes. Since the preparation of proteins containing a transmembrane domain or a prenylation motif is generally challenging an alternative membrane anchoring unit that is easy to attach, water-soluble and binds to different membrane mimetics would find broad application. The 33-residue long FATC domain of yeast TOR1 (y1fatc) fulfills these criteria and binds to neutral and negatively charged micelles, bicelles, and liposomes. As a case study, we fused it to the FKBP506-binding region of the protein FKBP38 (FKBP38-BD) and used H- N NMR spectroscopy to characterize localization of the chimeric protein to micelles, bicelles, and liposomes. Based on these and published data for y1fatc, its use as a C-terminally attachable membrane anchor for other proteins is compatible with a wide range of buffer conditions (pH circa 6-8.5, NaCl 0 to >150 mM, presence of reducing agents, different salts such as MgCl and CaCl ). The high water-solubility of y1fatc enables its use for titration experiments against a membrane-localized interaction partner of the fused target protein. Results from studies with peptides corresponding to the C-terminal 17-11 residues of the 33-residue long domain by 1D H NMR and CD spectroscopy indicate that they still can interact with membrane mimetics. Thus, they may be used as membrane anchors if the full y1fatc sequence is disturbing or if a chemically synthesized y1fatc peptide shall be attached by native chemical ligation, for example, unlabeled peptide to N-labeled target protein for NMR studies.

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Regulation of the Target of Rapamycin and Other Phosphatidylinositol 3-Kinase-Related Kinases by Membrane Targeting

Cited by 14 publications

References 150 publications

ATR-mediated regulation of nuclear and cellular plasticity

ATR-mediated regulation of nuclear and cellular plasticity

NMR– and MD simulation–based structural characterization of the membrane-associating FATC domain of ataxia telangiectasia mutated

Target of rapamycin FATC domain as a general membrane anchor: The FKBP‐12 like domain of FKBP38 as a case study

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