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Title: | CHANNELING & ALLOSTERY IN PDE-MEDIATED CYCLIC AMP SIGNAL TERMINATION | Authors: | NIKHIL KUMAR TULSIAN | Keywords: | Protein Kinase A, Phosphodiesterase, Substrate channeling, Hydrogen-deuterium exchange mass spectrometry, cyclic AMP signaling, enzyme kinetics | Issue Date: | 18-Aug-2016 | Citation: | NIKHIL KUMAR TULSIAN (2016-08-18). CHANNELING & ALLOSTERY IN PDE-MEDIATED CYCLIC AMP SIGNAL TERMINATION. ScholarBank@NUS Repository. | Abstract: | Spatiotemporal regulation of the cAMP signal is governed by both generation of cAMP by activation of adenylyl cyclases (activation phase) and through the hydrolysis of cAMP by phosphodiesterases (termination phase). Of the two phases, the termination phase is far less understood and involves assembly of PDEs with the cAMP receptor Protein Kinase A complexes called cAMP termination complexes. Through an analysis of dynamics and enzyme assays, my research has unraveled how the cAMP terminator complex accelerates cAMP turnover by allosterically channeling cAMP from its receptor to its hydrolase. The novel ‘channel’ is stabilized through peripheral protein-protein interactions and a central core mediated by cAMP/AMP ligand/product. Channeling in the PDE-PKA complex thus functions to mediate preferential responses to dynamic-levels of cAMP, rather than steady-state levels, thereby facilitating molecular adaptation in cAMP signaling. The channel in the cAMP terminator complex described offers an entirely new composite drug target for targeting cAMP signaling. | URI: | http://scholarbank.nus.edu.sg/handle/10635/134850 |
Appears in Collections: | Ph.D Theses (Open) |
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