Signal Transduction Mechanisms Of Pas And Hamp Domains

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The focus of my dissertation is on the signaling mechanisms employed by PAS and HAMP domains, which are widespread signaling modules that coordinate cellular metabolism with external stimuli. A subset of PAS domains directly sense external stimuli, through an associated cofactor or ligand, and regulate the activity of an attached effector domain. In contrast, HAMP domains do not sense external stimuli and serve as signal relay modules. They are typically associated with the membrane and relay extracellular signals into intracellular responses. A subset of HAMP domains, which occur in poly-HAMP chains, are not associated with the membrane and differ from canonical HAMP domains in the region responsible for signal input. To investigate HAMP domain signal transduction I have used the soluble receptor Aer2 as a model system. A unifying mechanism for HAMP domain signal transduction has yet to emerge, mainly due to lack of structural information. In chapter 1, I present the crystal structure of a 3-unit poly-HAMP chain from Aer2. Two distinct HAMP conformations were identified and a new model for signal transduction is presented. In Appendix 1, I present data that defines essential features of membrane associated HAMP domains. The results indicate that a signature motif: DExG, is required for HAMP domains to receive signal input across the membrane. PAS and HAMP domains can occur within the same protein. The best-studied example is the E. coli aerotaxis receptor Aer, where direct side-on PAS and HAMP domain interactions propagate signals downstream. In Chapter 3, I present a model for PAS and HAMP domain signal transduction in Aer2 that does not involve direct sideon interactions. This represents a new paradigm for applicable to successive PAS and HAMP domains and other similar signaling systems. One recent controversy, in the mammalian circadian clock, is the identification of two core clock genes, PER2 and nPAS2, as heme-binding PAS proteins. A complicated feedback mechanism has been suggested where cycles in heme availability feedback to regulate the activity of PER2 and nPAS2. In chapter 2, I present data that PER2-heme interactions are non-specific and not biologically relevant to the mammalian circadian clock.

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