Sandbox GGC16
From Proteopedia
PU.1
PU.1 is a hematopoietic transcription factor belonging to the Ets family of proteins. It regulates transcription of genes specific to myeloid and lymphoid cells, ultimately leading to cellular differentiation.[1] This transcription factor binds DNA with its helix-turn-helix motif, a common motif in transcription factors and DNA repair proteins.[2]
FunctionWithin the nucleus, PU.1 activates transcription of lymphoid genes by binding DNA during hematopoiesis. The name PU.1 comes from the protein's binding interactions with a purine-rich DNA sequence (5'-GAGGAA-3'). ActivationA post-translational modification of PU.1 occurs at serine residues, specifically, residues 140 and 146.[3] An experimental study also identified phosphorylation of serine 41 as a modification that induces activity. This phosphorylation is performed by protein kinase B (AKT).[4]
Binding DomainEts binding domain is conserved across the Ets family of proteins which consist of about 35 proteins with similar functions. In PU.1, this binding domain is located between residues 170 and 253. The binding domain is positively charged. Residues most closely interacting with DNA include Arginine and Lysine. These most highly conserved residues are the two Arginines on the central helix within the major groove of the DNA and two Lysines on the outer turns.[5] Other FunctionsDimerizationPU.1 can exhibit protein-protein interaction. As a transcription factor, it binds DNA as a monomer. However, it can dimerize on a longer, downstream binding site. Interestingly, other Ets family proteins that a structurally homologous cannot bind DNA in as a 2:1, dimer complex. A study suggested that the 2:1 complex formation could be a mechanism of auto-inhibition.[6] Other Protein InteractionsPU.1 can interact with GATA-1 and GATA-2, endothelial transcription factors responsible for erythroid development. This interaction has been observed to be antagonistic. This may likely play a big role in a stem cell's commitment to becoming an erythrocyte or leukocyte.[7] DiseasePU.1 has been identified as an oncogene. Mutations have been identified in patients with leukemias and lymphomas. Interestingly, the mutations are not always identified within the binding site. PEST domainThe PEST domain is adjacent to the binding domain, located between residues 116-165. This special domain has been found mutated in leukemia patients.[8] It is highly polar due to the abundance of proline, glutamate, serine, and threonine. Proteins with a PEST region typically have a short half-life of under 2 hours. It is believed that the PEST region is a tag for fast degradation of the protein. This mutation likely provides a mechanism for the protein to evade degradation, enabling it to continue inducing transcription. This could contribute to cancerous growth of white blood cells.
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