Modulation of the substrate specificity of the kinase PDK1 by distinct conformations of the full-length protein

Sacerdoti, Mariana; Gross, Lissy Zoe Florens; Riley, Andrew M.; Zehnder, Kathrin; Ghode, Abhijeet; Klinke, S.; Anand, Ganesh S.; Paris, Kristina A.; Winkel, Angelika F.; Herbrand, Amanda K.; Godage, H. Yasmin; Cozier, Gyles E.; Süß, Evelyn; Schulze, Jörg O.; Pastor-Flores, Daniel; Bollini, Mariela; Cappellari, María Victoria; Svergun, Dmitri I.; Graewert, Melissa A.; Aramendı́a, Pedro F.; Leroux, Alejandro E.; Potter, Barry V. L.; Camacho, Carlos J.; Biondi, Ricardo M.

doi:10.1126/scisignal.add3184

Cited by 9 publications

(3 citation statements)

References 98 publications

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“…PDK1 activity is known to be governed by several events: (i) translocation to the plasma membrane, (ii) post-translational modifications by phosphorylation, (iii) conformational changes, and (iv) interaction with different effectors ( Sacerdoti et al, 2023 ). We demonstrated that the overactivation of PDK1 in prion-infected neurons depends on the upstream kinase ROCK ( Alleaume-Butaux et al, 2015 ).…”

Section: Ptms Of Signaling Effectors Downstream Of Prp C ...mentioning

confidence: 99%

Post-translational modifications in prion diseases

Bizingre,

Bianchi,

Baudry

et al. 2024

Front. Mol. Neurosci.

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More than 650 reversible and irreversible post-translational modifications (PTMs) of proteins have been listed so far. Canonical PTMs of proteins consist of the covalent addition of functional or chemical groups on target backbone amino-acids or the cleavage of the protein itself, giving rise to modified proteins with specific properties in terms of stability, solubility, cell distribution, activity, or interactions with other biomolecules. PTMs of protein contribute to cell homeostatic processes, enabling basal cell functions, allowing the cell to respond and adapt to variations of its environment, and globally maintaining the constancy of the milieu interieur (the body’s inner environment) to sustain human health. Abnormal protein PTMs are, however, associated with several disease states, such as cancers, metabolic disorders, or neurodegenerative diseases. Abnormal PTMs alter the functional properties of the protein or even cause a loss of protein function. One example of dramatic PTMs concerns the cellular prion protein (PrPC), a GPI-anchored signaling molecule at the plasma membrane, whose irreversible post-translational conformational conversion (PTCC) into pathogenic prions (PrPSc) provokes neurodegeneration. PrPC PTCC into PrPSc is an additional type of PTM that affects the tridimensional structure and physiological function of PrPC and generates a protein conformer with neurotoxic properties. PrPC PTCC into PrPSc in neurons is the first step of a deleterious sequence of events at the root of a group of neurodegenerative disorders affecting both humans (Creutzfeldt–Jakob diseases for the most representative diseases) and animals (scrapie in sheep, bovine spongiform encephalopathy in cow, and chronic wasting disease in elk and deer). There are currently no therapies to block PrPC PTCC into PrPSc and stop neurodegeneration in prion diseases. Here, we review known PrPC PTMs that influence PrPC conversion into PrPSc. We summarized how PrPC PTCC into PrPSc impacts the PrPC interactome at the plasma membrane and the downstream intracellular controlled protein effectors, whose abnormal activation or trafficking caused by altered PTMs promotes neurodegeneration. We discussed these effectors as candidate drug targets for prion diseases and possibly other neurodegenerative diseases.

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Section: Ptms Of Signaling Effectors Downstream Of Prp C ...mentioning

confidence: 99%

Post-translational modifications in prion diseases

Bizingre,

Bianchi,

Baudry

et al. 2024

Front. Mol. Neurosci.

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“…24 PIP 3 -mediated activation of PDK1 stimulates AKT phosphorylation, which subsequently inhibits a negative regulator, the tuberous sclerosis complex (TSC). 25–28 In signaling, TSC acts as the GTPase activating protein (GAP) and inhibits GTP-bound Ras homolog enriched in brain protein (RHEB, a member of the Ras superfamily). 29,30 Thus, AKT-mediated inhibition of TSC promotes RHEB activation.…”

Section: Introductionmentioning

confidence: 99%

The allosteric mechanism of mTOR activation can inform bitopic inhibitor optimization

Liu,

Zhang,

Jang

et al. 2024

Chem. Sci.

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“…Protein phosphorylation and dephosphorylation of tyrosine, serine, and threonine are two critical enzymatic processes that control signal transduction pathways activated by growth factors, cytokines, and integrins. − Kinases perform phosphorylation, while phosphatases execute hydrolysis by removing the phosphate group from phosphorylated residues. The cytoplasmic region of receptor tyrosine kinases (RTKs) includes the kinase domain and the unstructured C-terminal tail.…”

Section: Introductionmentioning

confidence: 99%

SHP2–EGFR States in Dephosphorylation Can Inform Selective SHP2 Inhibitors, Dampening RasGAP Action

Liu,

Jang,

Nussinov

2024

J. Phys. Chem. B

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SHP2 is a positive regulator of the EGFR-dependent Ras/MAPK pathway. It dephosphorylates a regulatory phosphorylation site in EGFR that serves as the binding site to RasGAP (RASA1 or p120RasGAP). RASA1 is activated by binding to the EGFR phosphate group. Active RASA1 deactivates Ras by hydrolyzing Ras-bound GTP to GDP. Thus, SHP2 dephosphorylation of EGFR effectively prevents RASA1-mediated deactivation of Ras, thereby stimulating proliferation. Despite knowledge of this vital regulation in cell life, mechanistic in-depth structural understanding of the involvement of SHP2, EGFR, and RASA1 in the Ras/MAPK pathway has largely remained elusive. Here we elucidate the interactions, the factors influencing EGFR’s recruitment of RASA1, and SHP2’s recognition of the substrate site in EGFR. We reveal that RASA1 specifically interacts with the DEpY992LIP motif in EGFR featuring a proline residue at the +3 position C-terminal to pY primarily through its nSH2 domain. This interaction is strengthened by the robust attraction of two acidic residues, E991 and D990, of EGFR to two basic residues in the BC-loop near the pY-binding pocket of RASA1’s nSH2. In the stable precatalytic state of SHP2 with EGFR (DADEpY992LIPQ), the E-loop of SHP2’s active site favors the interaction with the (−2)-position D990 and (−4)-position D988 N-terminal to pY992 in EGFR, while the pY-loop constrains the (+4)-position Q996 C-terminal to pY992. These specific interactions not only provide a structural basis for identifying negative regulatory sites in other RTKs but can inform selective, high-affinity active-site SHP2 inhibitors tailored for SHP2 mutants.

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Modulation of the substrate specificity of the kinase PDK1 by distinct conformations of the full-length protein

Cited by 9 publications

References 98 publications

Post-translational modifications in prion diseases

Post-translational modifications in prion diseases

The allosteric mechanism of mTOR activation can inform bitopic inhibitor optimization

SHP2–EGFR States in Dephosphorylation Can Inform Selective SHP2 Inhibitors, Dampening RasGAP Action

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