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    Computational investigation of peripheral membrane protein "Pleckstrin homology domain" and its regulation

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    Author
    Jha, Kirtika
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    Abstract
    The peripheral membrane protein repertoire is around 25% composed of the Pleckstrin homology domain (PHD). PHD are component of the multidomain protein and plays the role of an adaptor in recruitment of these proteins onto the bilayer. Because of their specificity in binding to particular membrane constituents, including phosphoinositides, these PHDs are referred to as "conditional" peripheral membrane proteins. They play important role in the regulation of the pathway in which they participate. Akt1-PHD and Dynamin PHD are the two distinct PHDs involved in different pathways have been examined in this thesis project. A crucial component of the Akt1-PIP3 signaling pathway is Akt1-PHD. In normal conditions, Akt1-PHD only attaches to PIP3, but when a charged mutation (E17K) occurs, it also begins to bind to PIP2 (PIP2 exclusion). These PIP lipids can adopt various protonation states according to their surroundings, leading to a variety of protonated states. This study examines the impact of varying lipid protonation states on the membrane attachment of Akt1-PHD in both wild-type and mutant protein states at the molecular level. This offers a thorough understanding of how the different protonation states of PIP lipids regulate the signaling pathway. A pathway has been created in a different work to investigate a non- canonical post-translational modification in a molecular dynamics simulation. Investigations have been conducted on the ADP-ribosylation of Akt1-PHD at experimentally determined putative residue locations. The observed experimental result has been explained at the molecular level. Its potential function in the pathway's regulation is demonstrated by the thorough examination of modifications that are comparable at several PHD sites. Furthermore, a novel variable loop (referred to as VL4) has been identified and its functional role demonstrated in the other work involving dynamin PHD. Application of a coarse graining technique i.e. Hetero elastic network model (HENM) has been described in detail and applied to a few proteins, such as dynamin, EHD, SNX1 etc.
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    https://etd.iisc.ac.in/handle/2005/6524
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    • Molecular Biophysics Unit (MBU) [301]

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