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Understanding the hyper-activation among the recurrent oncogenic miss-sense mutations in NSD2 methyltransferaseHincapié-Otero, María Mercedes 03 1900 (has links)
Mutations in epigenetic regulators such as the SET domain-containing methyltransferase NSD2 are of high interest among the research community nowadays. The involvement of this mutations in multiple diseases put them in the spotlight. Interestingly, the change of the glutamic acid residue in the position 1099 of the NSD2 SET domain for a lysine residue has been recurrently found in multiple myeloma patients. This mutation produces a hyperactive enzyme that hypermethylate the natural enzymatic substrate: the lysine in the position 36 of the basic tail of the histone 3 in the nucleosomal context. Apparently, this hyperactivation may be related to the disruption of a critical salt-bridge that stabilize an autoregulatory loop of the NSD2 catalytic site. However, despite the extensive research that have been done around this phenomenon, the molecular mechanism behind this hyperactivation still remains unknow. For this reason, in this study we addressed this matter from a structural point of view by evaluating the structure and dynamics of the protein in solution by high-resolution Nuclear Magnetic Resonance (NMR) spectroscopy and biophysical techniques. We found increased local segmental motions in us to ms timescale that induced protein flexibility that may correlate with gain-of-function of E1099K miss-sense mutation. Further functional studies with the native substrates in vitro and in vivo are needed to understand this observation.
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Toward Understanding the Mechanisms of of Lipid Sensitivity in Pentameric Ligand-Gated Ion ChannelsLabriola, Jonathan 23 September 2013 (has links)
Pentameric ligand-gated ion channels (pLGICs) are membrane bound receptors found in the nervous system. They are responsible for detecting neurotransmitters released from neurons and subsequently mediating responses of the cells on which they are found. Thus, pLGICs play an invaluable role in communication between cells of the nervous system and understanding their function is pivotal to understanding how the nervous system works in general. One factor which is known to mediate pLGIC function is lipids found in the membrane environment in which pLGICs are embedded. This dissertation explores the various ways in which lipids interact with and modulate the function of pLGIC. Potential mechanisms and biological consequences of this modulation will be presented and discussed within the context of our current state of knowledge of pLGIC and nervous system function.
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Toward Understanding the Mechanisms of of Lipid Sensitivity in Pentameric Ligand-Gated Ion ChannelsLabriola, Jonathan January 2013 (has links)
Pentameric ligand-gated ion channels (pLGICs) are membrane bound receptors found in the nervous system. They are responsible for detecting neurotransmitters released from neurons and subsequently mediating responses of the cells on which they are found. Thus, pLGICs play an invaluable role in communication between cells of the nervous system and understanding their function is pivotal to understanding how the nervous system works in general. One factor which is known to mediate pLGIC function is lipids found in the membrane environment in which pLGICs are embedded. This dissertation explores the various ways in which lipids interact with and modulate the function of pLGIC. Potential mechanisms and biological consequences of this modulation will be presented and discussed within the context of our current state of knowledge of pLGIC and nervous system function.
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Theoretical Prediction of Changes in Protein Structural Stability upon Cosolvent or Salt Addition and Amino-acid Mutation / 共溶媒や塩の添加およびアミノ酸置換に伴う蛋白質立体構造安定性変化の理論的予測Murakami, Shota 23 March 2017 (has links)
京都大学 / 0048 / 新制・課程博士 / 博士(エネルギー科学) / 甲第20481号 / エネ博第350号 / 新制||エネ||70(附属図書館) / 京都大学大学院エネルギー科学研究科エネルギー基礎科学専攻 / (主査)教授 木下 正弘, 教授 森井 孝, 教授 片平 正人 / 学位規則第4条第1項該当 / Doctor of Energy Science / Kyoto University / DFAM
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