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dc.contributor.authorKarp, Jerome M.
dc.date.accessioned2018-07-12T17:01:35Z
dc.date.available2018-07-12T17:01:35Z
dc.date.issued2016
dc.identifier.citationSource: Dissertation Abstracts International, Volume: 78-03(E), Section: B.;Advisors: David Cowburn.
dc.identifier.urihttps://yulib002.mc.yu.edu/login?url=http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:10291782
dc.identifier.urihttps://hdl.handle.net/20.500.12202/392
dc.description.abstractNumerous proteins in the cell are intrinsically disordered proteins (IDPs), and even many structured proteins contain disordered regions that mediate important physiological functions. In this thesis, we explore two protein systems, each featuring disorder which contributes to the protein's functionality.;First, we study the fibroblast growth factor receptor 2 (FGFR2) kinase, a receptor tyrosine kinase (RTK) which activates several signaling pathways in the cell. The catalytic activity of FGFR2 kinase is regulated by phosphorylation of the "activation loop," a conserved disordered motif in RTKs, but the precise mechanism of regulation is unknown. We use a variety of enhanced-sampling molecular dynamics (MD) simulations to address this question. We find that phosphorylation of the kinase favors two other conformational changes near the kinase's active site. First, Leu665 and Pro666 point away from the active site, enabling the kinase's substrate to bind. Second, Arg664 moves inward and interacts with the ATP molecule bound in the active site, locking the substrate tyrosine and ATP in a precise position and favoring catalysis. Our model suggests that phosphorylation of Tyr657 in FGFR2 kinase actively promotes substrate catalysis by altering the conformational dynamics of the kinase to favor the phosphotransferase reaction.;Second, we examine the interaction between the transport factor NTF2 and an FG Nup that comprises part of the nuclear pore complex (NPC). The NPC mediates nucleocytoplasmic transport, preventing macromolecules from passing through unless they are bound to a transport factor. The FG Nups are integral to this complex, containing phenylalanine-glycine (FG) repeats that mediate the interaction between the Nups and transport factors. The interaction is specific, yet transport is exceptionally fast. To explain this paradox, we show that FG repeats slide along the hydrophobic patches of NTF2, enabling one repeat to slide off the transport factor while another slides on. Additionally, spacers between the FG repeats behave as "entropic springs," disfavoring static binding of the FG repeats. These features allow specific albeit dynamic interaction between the FG Nups and the transport factors, yet enable rapid transport. Our model highlights the important role that the disordered regions play in mediating this important cellular function.
dc.publisherProQuest Dissertations & Theses
dc.subjectBiophysics.
dc.subjectBiochemistry.
dc.titleUsing enhanced sampling molecular dynamics simulations to investigate the roles of disordered regions in proteins
dc.typeDissertation


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