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(2012)Journal ArticleThe CACCC-box binding protein erythroid Krüppel-like factor (EKLF/KLF1) is a master regulator that directs the expression of many important erythroid genes. We have previously shown that EKLF drives transcription of the gene for a second KLF, basic Krüppel-like factor, or KLF3. We have now tested the in vivo role of KLF3 in erythroid cells by examining Klf3 knockout mice. KLF3-deficient adults exhibit a mild compensated anemia, including enlarged spleens, increased red pulp, and a higher percentage of erythroid progenitors, together with elevated reticulocytes and abnormal erythrocytes in the peripheral blood. Impaired erythroid maturation is also observed in the fetal liver. We have found that KLF3 levels rise as erythroid cells mature to become TER119(+). Consistent with this, microarray analysis of both TER119(-) and TER119(+) erythroid populations revealed that KLF3 is most critical at the later stages of erythroid maturation and is indeed primarily a transcriptional repressor. Notably, many of the genes repressed by KLF3 are also known to be activated by EKLF. However, the majority of these are not currently recognized as erythroid-cell-specific genes. These results reveal the molecular and physiological function of KLF3, defining it as a feedback repressor that counters the activity of EKLF at selected target genes to achieve normal erythropoiesis.
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(2023)ThesisThe self-assembly of proteins into intricate high-order structures can be harnessed for the precise positioning of functional molecules in nanotechnology. The organisation of enzymes on protein scaffolds has been previously shown to enhance enzyme catalytic activity. Additionally, the alignment of metal-binding proteins, known as metalloproteins, on filamentous proteins has been exploited to produce electrically conductive nanowires. The focus of this thesis is on the development of improved biosynthetic strategies for the creation of multifunctional nanomaterials by harnessing the self-assembly of filamentous proteins. Central to the engineering in this thesis is prefoldin, which is a molecular chaperone from archaea with the ability to self-assemble into hetero-hexameric complexes and filamentous structures. Prefoldin proteins exhibits high thermal stability and have engineerable interfaces for bioconjugation of functional proteins. Therefore, the research goal of this thesis was to engineer robust and modular protein scaffolds for the precise position of enzymes and alignment of electrically conductive subunits to create biocatalysis and bioelectronic systems. The first aim of the research was to construct a protein scaffold from a hexameric self-assembling protein and immobilise enzymes on the protein scaffold to examine for enhanced sequential catalytic reactions. The second aim explored the capability of prefoldin filaments to align various metalloproteins in proximity over large distances for electron transfer. Distinct metalloproteins were exploited to create nanowires with various electronic properties for applications in bioelectronic devices. The third aim developed a strategy to localise redox enzymes at either end of the metalloprotein nanowires and potentially demonstrate energy transfer along the nanowire between enzymes undergoing redox reactions. The successful achievement of these aims establishes a biostrategy to use a controllable and modular prefoldin protein scaffold for the fabrication of biocatalysis and bioelectronic devices.