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\n\n \n \n \n \n \n \n The structural basis of Akt PH domain interaction with calmodulin.\n \n \n \n \n\n\n \n Weako, J.; Jang, H.; Keskin, O.; Nussinov, R.; and Gursoy, A.\n\n\n \n\n\n\n
Biophysical Journal. 2021.\n
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@article{WEAKO2021,\n author = "Weako, Jackson and Jang, Hyunbum and Keskin, Ozlem and Nussinov, Ruth and Gursoy, Attila",\n title = "The structural basis of Akt PH domain interaction with calmodulin",\n journal = "Biophysical Journal",\n year = "2021",\n issn = "0006-3495",\n doi = "https://doi.org/10.1016/j.bpj.2021.03.018",\n url = "https://www.sciencedirect.com/science/article/pii/S0006349521002484",\n abstract = "Akt plays a key role in the Ras/PI3K/Akt/mTOR signaling pathway. In breast cancer, Akt translocation to the plasma membrane is enabled by the interaction of its pleckstrin homology domain (PHD) with calmodulin (CaM). At the membrane, the conformational change promoted by PIP3 releases CaM and facilitates Thr308 and Ser473 phosphorylation and activation. Here, using modeling and molecular dynamics simulations, we aim to figure out how CaM interacts with Akt’s PHD at the atomic level. Our simulations show that CaM-PHD interaction is thermodynamically stable and involves a β-strand rather than an α-helix, in agreement with NMR data, and that electrostatic and hydrophobic interactions are critical. The PHD interacts with CaM lobes; however, multiple modes are possible. IP4, the polar head of PIP3, weakens the CaM-PHD interaction, implicating the release mechanism at the plasma membrane. Recently, we unraveled the mechanism of PI3Kα activation at the atomistic level and the structural basis for Ras role in the activation. Here, our atomistic structural data clarify the mechanism of how CaM interacts, delivers, and releases Akt—the next node in the Ras/PI3K pathway—at the plasma membrane.",\n keywords = "CBM"\n}\n\n
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\n Akt plays a key role in the Ras/PI3K/Akt/mTOR signaling pathway. In breast cancer, Akt translocation to the plasma membrane is enabled by the interaction of its pleckstrin homology domain (PHD) with calmodulin (CaM). At the membrane, the conformational change promoted by PIP3 releases CaM and facilitates Thr308 and Ser473 phosphorylation and activation. Here, using modeling and molecular dynamics simulations, we aim to figure out how CaM interacts with Akt’s PHD at the atomic level. Our simulations show that CaM-PHD interaction is thermodynamically stable and involves a β-strand rather than an α-helix, in agreement with NMR data, and that electrostatic and hydrophobic interactions are critical. The PHD interacts with CaM lobes; however, multiple modes are possible. IP4, the polar head of PIP3, weakens the CaM-PHD interaction, implicating the release mechanism at the plasma membrane. Recently, we unraveled the mechanism of PI3Kα activation at the atomistic level and the structural basis for Ras role in the activation. Here, our atomistic structural data clarify the mechanism of how CaM interacts, delivers, and releases Akt—the next node in the Ras/PI3K pathway—at the plasma membrane.\n
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\n\n \n \n \n \n \n \n Neuropsychiatric Symptoms of COVID-19 Explained by SARS-CoV-2 Proteins’ Mimicry of Human Protein Interactions.\n \n \n \n \n\n\n \n Yapici-Eser, H.; Koroglu, Y. E.; Oztop-Cakmak, O.; Keskin, O.; Gursoy, A.; and Gursoy-Ozdemir, Y.\n\n\n \n\n\n\n
Frontiers in Human Neuroscience, 15: 126. 2021.\n
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@article{10.3389/fnhum.2021.656313,\n author = "Yapici-Eser, Hale and Koroglu, Yunus Emre and Oztop-Cakmak, Ozgur and Keskin, Ozlem and Gursoy, Attila and Gursoy-Ozdemir, Yasemin",\n title = "Neuropsychiatric Symptoms of COVID-19 Explained by SARS-CoV-2 Proteins’ Mimicry of Human Protein Interactions",\n journal = "Frontiers in Human Neuroscience",\n volume = "15",\n pages = "126",\n year = "2021",\n url = "https://www.frontiersin.org/article/10.3389/fnhum.2021.656313",\n doi = "10.3389/fnhum.2021.656313",\n issn = "1662-5161",\n abstract = "The first clinical symptoms focused on the presentation of coronavirus disease 2019 (COVID-19) have been respiratory failure, however, accumulating evidence also points to its presentation with neuropsychiatric symptoms, the exact mechanisms of which are not well known. By using a computational methodology, we aimed to explain the molecular paths of COVID-19 associated neuropsychiatric symptoms, based on the mimicry of the human protein interactions with SARS-CoV-2 proteins.Methods: Available 11 of the 29 SARS-CoV-2 proteins’ structures have been extracted from Protein Data Bank. HMI-PRED (Host-Microbe Interaction PREDiction), a recently developed web server for structural PREDiction of protein-protein interactions (PPIs) between host and any microbial species, was used to find the “interface mimicry” through which the microbial proteins hijack host binding surfaces. Classification of the found interactions was conducted using the PANTHER Classification System.Results: Predicted Human-SARS-CoV-2 protein interactions have been extensively compared with the literature. Based on the analysis of the molecular functions, cellular localizations and pathways related to human proteins, SARS-CoV-2 proteins are found to possibly interact with human proteins linked to synaptic vesicle trafficking, endocytosis, axonal transport, neurotransmission, growth factors, mitochondrial and blood-brain barrier elements, in addition to its peripheral interactions with proteins linked to thrombosis, inflammation and metabolic control.Conclusion: SARS-CoV-2-human protein interactions may lead to the development of delirium, psychosis, seizures, encephalitis, stroke, sensory impairments, peripheral nerve diseases, and autoimmune disorders. Our findings are also supported by the previous in vivo and in vitro studies from other viruses. Further in vivo and in vitro studies using the proteins that are pointed here, could pave new targets both for avoiding and reversing neuropsychiatric presentations.",\n keywords = "CBM"\n}\n\n
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\n The first clinical symptoms focused on the presentation of coronavirus disease 2019 (COVID-19) have been respiratory failure, however, accumulating evidence also points to its presentation with neuropsychiatric symptoms, the exact mechanisms of which are not well known. By using a computational methodology, we aimed to explain the molecular paths of COVID-19 associated neuropsychiatric symptoms, based on the mimicry of the human protein interactions with SARS-CoV-2 proteins.Methods: Available 11 of the 29 SARS-CoV-2 proteins’ structures have been extracted from Protein Data Bank. HMI-PRED (Host-Microbe Interaction PREDiction), a recently developed web server for structural PREDiction of protein-protein interactions (PPIs) between host and any microbial species, was used to find the “interface mimicry” through which the microbial proteins hijack host binding surfaces. Classification of the found interactions was conducted using the PANTHER Classification System.Results: Predicted Human-SARS-CoV-2 protein interactions have been extensively compared with the literature. Based on the analysis of the molecular functions, cellular localizations and pathways related to human proteins, SARS-CoV-2 proteins are found to possibly interact with human proteins linked to synaptic vesicle trafficking, endocytosis, axonal transport, neurotransmission, growth factors, mitochondrial and blood-brain barrier elements, in addition to its peripheral interactions with proteins linked to thrombosis, inflammation and metabolic control.Conclusion: SARS-CoV-2-human protein interactions may lead to the development of delirium, psychosis, seizures, encephalitis, stroke, sensory impairments, peripheral nerve diseases, and autoimmune disorders. Our findings are also supported by the previous in vivo and in vitro studies from other viruses. Further in vivo and in vitro studies using the proteins that are pointed here, could pave new targets both for avoiding and reversing neuropsychiatric presentations.\n
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