8bzm
FOXK1-ELF1-heterodimer bound to DNA
Structural highlights
FunctionFOXK1_HUMAN Transcriptional regulator involved in different processes such as glucose metabolism, aerobic glycolysis, muscle cell differentiation and autophagy (By similarity). Recognizes and binds the forkhead DNA sequence motif (5'-GTAAACA-3') and can both act as a transcription activator or repressor, depending on the context (PubMed:17670796). Together with FOXK2, acts as a key regulator of metabolic reprogramming towards aerobic glycolysis, a process in which glucose is converted to lactate in the presence of oxygen (By similarity). Acts by promoting expression of enzymes for glycolysis (such as hexokinase-2 (HK2), phosphofructokinase, pyruvate kinase (PKLR) and lactate dehydrogenase), while suppressing further oxidation of pyruvate in the mitochondria by up-regulating pyruvate dehydrogenase kinases PDK1 and PDK4 (By similarity). Probably plays a role in gluconeogenesis during overnight fasting, when lactate from white adipose tissue and muscle is the main substrate (By similarity). Involved in mTORC1-mediated metabolic reprogramming: in response to mTORC1 signaling, translocates into the nucleus and regulates the expression of genes associated with glycolysis and downstream anabolic pathways, such as HIF1A, thereby regulating glucose metabolism (By similarity). Together with FOXK2, acts as a negative regulator of autophagy in skeletal muscle: in response to starvation, enters the nucleus, binds the promoters of autophagy genes and represses their expression, preventing proteolysis of skeletal muscle proteins (By similarity). Acts as a transcriptional regulator of the myogenic progenitor cell population in skeletal muscle (By similarity). Binds to the upstream enhancer region (CCAC box) of myoglobin (MB) gene, regulating the myogenic progenitor cell population (By similarity). Promotes muscle progenitor cell proliferation by repressing the transcriptional activity of FOXO4, thereby inhibiting myogenic differentiation (By similarity). Involved in remodeling processes of adult muscles that occur in response to physiological stimuli (By similarity). Required to correct temporal orchestration of molecular and cellular events necessary for muscle repair (By similarity). Represses myogenic differentiation by inhibiting MEFC activity (By similarity). Positively regulates Wnt/beta-catenin signaling by translocating DVL into the nucleus (PubMed:25805136). Reduces virus replication, probably by binding the interferon stimulated response element (ISRE) to promote antiviral gene expression (PubMed:25852164). Accessory component of the polycomb repressive deubiquitinase (PR-DUB) complex; recruits the PR-DUB complex to specific FOXK1-bound genes (PubMed:24634419, PubMed:30664650).[UniProtKB:P42128][1] [2] [3] [4] [5] Publication Abstract from PubMedIn the same way that the mRNA-binding specificities of transfer RNAs define the genetic code, the DNA-binding specificities of transcription factors (TFs) form the molecular basis of the gene regulatory code(1,2). The human gene regulatory code is much more complex than the genetic code, in particular because there are more than 1,600 TFs that commonly interact with each other. TF-TF interactions are required for specifying cell fate and executing cell-type-specific transcriptional programs. Despite this, the landscape of interactions between DNA-bound TFs is poorly defined. Here we map the biochemical interactions between DNA-bound TFs using CAP-SELEX, a method that can simultaneously identify individual TF binding preferences, TF-TF interactions and the DNA sequences that are bound by the interacting complexes. A screen of more than 58,000 TF-TF pairs identified 2,198 interacting TF pairs, 1,329 of which preferentially bound to their motifs arranged in a distinct spacing and/or orientation. We also discovered 1,131 TF-TF composite motifs that were markedly different from the motifs of the individual TFs. In total, we estimate that the screen identified between 18% and 47% of all human TF-TF motifs. The novel composite motifs we found were enriched in cell-type-specific elements, active in vivo and more likely to be formed between developmentally co-expressed TFs. Furthermore, TFs that define embryonic axes commonly interacted with different TFs and bound to distinct motifs, explaining how TFs with a similar specificity can define distinct cell types along developmental axes. DNA-guided transcription factor interactions extend human gene regulatory code.,Xie Z, Sokolov I, Osmala M, Yue X, Bower G, Pett JP, Chen Y, Wang K, Cavga AD, Popov A, Teichmann SA, Morgunova E, Kvon EZ, Yin Y, Taipale J Nature. 2025 Apr 9. doi: 10.1038/s41586-025-08844-z. PMID:40205063[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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