Doctor of Philosophy (PhD)
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globin, GbX, ZnPPIX, Ngb, Cygb, CO, O2
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Cytoglobin (Cygb), neuroglobin (Ngb), and globin X (GbX) belongs to recently discovered members of the vertebrate globin family, they carry a heme prosthetic group that can reversibly bind exogenous ligands such as CO, NO and O2. Although the physiological functions of Cygb, Ngb and GbX are still under debate, several possible physiological functions for these proteins were proposed. Cytoglobin was reported to participate in lipid-based signaling and to stabilize the tumor suppressor p53 upon DNA damage, which imply its anti-cancer role. Neuroglobin was shown to interact with α-subunit of the heterotrimeric G protein as well as cytochrome c which indicates a role in cell apoptosis. Both proteins were also proposed to participate in NO metabolism. Compared to the well-known vertebrate globin, hemoglobin and myoglobin, the new members have several distinct structural characteristics. First, unlike Hb and Mb, the distal histidine coordinates with the heme iron at the sixth axial position in Cygb, Ngb and GbX, forming a hexa-coordinated heme iron and thus regulating kinetics and equilibrium constants for exogenous ligand binding to heme. Second, an oxidation/reduction of an intramolecular disulfide bridge which is found in all three hexa-coordinated globins, also modulates affinity for diatomic ligands such as O2 and CO. Additionally, both Cygb and GbX are found to have extended N- and C- terminals with unclear function, although the N-terminal in GbX proposed to be involved in the protein binding to the membrane. The work presented in this dissertation focuses on investigation of the role of internal ligand (distal histidine) and disulfide bridge on structure-function relationships in GbX, in terms of regulating affinity and kinetics for small diatomic ligands. Indeed, we shown a very weak ligand binding to heme iron in GbX, suggesting its district role among heaxa-coordiante vertebrate globins. In addition, the study of conformation dynamics that affect the heme cavity accessibility of Cygb and Ngb by incorporate heme fluorescent analogy ZnPPIX into the protein is also performed. These data shown a high conformational heterogeneity of the distal pocket in hexa-coordiante globins as well as increased accessibility of the heme pocket in Ngb.
Lei, Ruipeng, "Structure Function Relationship in Hexacoordinate Heme Proteins: Mechanism of Globin X Interactions with Exogenous Ligands and Ligand Accessiblity in Cytoglobin and Neuroglobin" (2020). FIU Electronic Theses and Dissertations. 4470.
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