Structure of the Forkhead Domain of FOXP2 Bound to DNA

Stroud, James C.; Wu, Yongqing; Bates, D.L.; Han, Aidong; Nowick, Katja; Pääbo, Svante; Tong, Harry; Chen, Lin

doi:10.1016/j.str.2005.10.005

Cited by 174 publications

(271 citation statements)

References 41 publications

(64 reference statements)

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“…Our computer search based on a motif scan identified both cdc2 and cdk5 kinases as candidates under very strict conditions (http:͞͞scansite.mit.edu). It has been also very recently suggested that FOXP dimers can bind cognate DNA sites separated far from each other or located on different DNA strands, possibly suggesting that the function of FOXP3 proteins for certain genes (e.g., cytokines affected in our study) highly depends on promoting the assembly of higher-order protein-DNA complexes with varying degrees (23).…”

Section: Discussionmentioning

confidence: 54%

The mutant leucine-zipper domain impairs both dimerization and suppressive function of Foxp3 in T cells

Chae

Henegariu

Lee

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Regulatory T cells that express the Foxp3 transcription factor play important roles in preventing autoimmune diseases. Although several studies have demonstrated that the lack of the forkhead DNA-binding domain of Foxp3 caused severe autoimmune disease in scurfy mutant mice, the other functional domains of Foxp3 are less well characterized. Here, we show that the deletion of glutamic acid (⌬E250) in the leucine-zipper domain of Foxp3 causes a loss of hyporesponsiveness when compared with wild-type Foxp3 upon antigenic stimulation. CD4 T cells that ectopically express the glutamic acid mutant show significant losses of suppressor activity both in vitro and in vivo. We also demonstrate that regulation of both Th1-and Th2-type cytokine secretion in CD4 T cells that express wild-type Foxp3 is significantly altered by the deletion of glutamic acid. Defects are also observed in the expression of adhesion molecules, such as L-selectin (CD62L) and CD103, suggesting an important role of glutamic acid in the migratory behavior of regulatory T cells. Finally, this mutation reduces transcriptional repressor activity and impairs the homodimerization of Foxp3. Taken together, our results provide insight into the mechanism that controls autoimmune diseases via the deletion of this single glutamic acid residue in the leucine-zipper domain of Foxp3. autoimmunity R egulatory T cells are known to play key roles in the maintenance of immunological homeostasis by the suppression of potential self-reactive CD4ϩCD25Ϫ T cells in the periphery (1). Naturally arising CD4ϩCD25ϩ T cells isolated from both mouse and human show similar behaviors in terms of potent suppressive functions on their CD25Ϫ counterparts via cell-cell contact (2, 3).Recent studies on CD4ϩCD25ϩ T cells have shown that Foxp3, a forkhead (FKH) family transcription factor, has an important role in regulatory T cell development and is currently the best lineage marker in mice (4). In addition, Foxp3-expressing regulatory T cells themselves are hyporesponsive to antigenic stimulation for both proliferation and inhibition of cytokine secretion (4, 5). Transgenic and knockout studies of Foxp3 revealed that Foxp3 plays a critical role for the prevention of autoimmune disease, adoptive transfer of Foxp3-expressing CD4 T cells have also demonstrated that ectopic expression of Foxp3 is sufficient for the mediation of immunological tolerance in vivo (5-7).In humans, it has been shown that Foxp3 mutations are responsible for Ϸ70% of patients with severe X-linked autoimmunity and allergic disorders in immune dysfunction polyendocrinopathy enteropathy X-linked (IPEX). The onset of similar autoimmune disease occurs in scurfy mutant mice that lacks the important FKH-binding domain in Foxp3 because of the presence of a 2-bp insertion that results in an early stop codon (8-10). Although members of the Fox family can act as transcriptional activators and repressors, it has been shown experimentally that the FKH domain of Foxp3 is required for the suppression of various cytokine genes (1...

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Section: Discussionmentioning

confidence: 54%

The mutant leucine-zipper domain impairs both dimerization and suppressive function of Foxp3 in T cells

Chae

Henegariu

Lee

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…S1B). Most notably we found that in the positions that have been identified as essential for domain-swap dimerization (11,12), the Fkh1/2 residues are similar or identical to those of the FoxP subfamily and not to those of the classical monomeric Fox proteins from mammals or yeast (Fig. 1A and Fig.…”

Section: Significancementioning

confidence: 93%

“…10). Whereas most forkhead domains bind DNA as monomers, crystallographic and biochemical studies of members of the human FoxP family have revealed that the forkhead domains of FoxP2 and FoxP3 form homodimers, in vitro and likely in vivo, through an exchange of corresponding domains (or subdomains) between monomers, referred to as domain-swapped dimers (11)(12)(13). Because Fkh1 and/or Fkh2 (Fkh1/2) have been shown to regulate origin firing through binding in cis to origins, Fkh1/2 dimerization would potentially provide a mechanism for clustering two or more Fkh1/2-bound origins in trans (14).…”

mentioning

confidence: 99%

Conserved forkhead dimerization motif controls DNA replication timing and spatial organization of chromosomes in S. cerevisiae

Ostrow

Kalhor

Gan

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Forkhead Box (Fox) proteins share the Forkhead domain, a wingedhelix DNA binding module, which is conserved among eukaryotes from yeast to humans. These sequence-specific DNA binding proteins have been primarily characterized as transcription factors regulating diverse cellular processes from cell cycle control to developmental fate, deregulation of which contributes to developmental defects, cancer, and aging. We recently identified Saccharomyces cerevisiae Forkhead 1 (Fkh1) and Forkhead 2 (Fkh2) as required for the clustering of a subset of replication origins in G 1 phase and for the early initiation of these origins in the ensuing S phase, suggesting a mechanistic role linking the spatial organization of the origins and their activity. Here, we show that Fkh1 and Fkh2 share a unique structural feature of human FoxP proteins that enables FoxP2 and FoxP3 to form domain-swapped dimers capable of bridging two DNA molecules in vitro. Accordingly, Fkh1 self-associates in vitro and in vivo in a manner dependent on the conserved domain-swapping region, strongly suggestive of homodimer formation. Fkh1-and Fkh2-domain-swap-minus (dsm) mutations are functional as transcription factors yet are defective in replication origin timing control. Fkh1-dsm binds replication origins in vivo but fails to cluster them, supporting the conclusion that Fkh1 and Fkh2 dimers perform a structural role in the spatial organization of chromosomal elements with functional importance.DNA replication timing | chromatin | nuclear organization | Fox proteins | DNA binding protein F undamental processes of DNA repair, recombination, transcription, and replication often occur in specific subnuclear domains or in localized foci (reviewed in refs. 1-4). In yeast for example, hundreds of highly expressed tRNA genes coalesce into multiple foci, each containing several active tRNA genes (reviewed in ref. 5). Similarly, hundreds of replication origins coalesce into foci containing several origins each, which become bidirectional replisomes that remain colocalized as DNA is spooled through during replication (reviewed in ref. 6). Such spatial organization is thought to contribute to the efficiency of these processes by increasing the local concentration of the involved factors, which may consequently also exclude competing or interfering factors or processes. How distal DNA sequences are assembled into these structures is poorly understood.We recently identified the Saccharomyces cerevisiae transcription factors Forkhead 1 (Fkh1) and Forkhead 2 (Fkh2) as being required for the clustering of a subset of replication origins in G 1 phase and for the early initiation of these origins in the ensuing S phase (7). How Fkh1 and Fkh2 promote clustering is unclear; however, their binding near origins might promote origin-origin interactions through binding to other proteins at origins, such as the origin recognition complex (ORC) (7). Fkh1 has also been implicated as a regulator of mating-type switching, which involves homologous recombination between distal chr...

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“…The first site is located at the N terminus, the second one in the forkhead domain and the last one between NLS and NES (Figures 1 and 2). The second AKT/PKB phosphorylation site is located in the wing W2 of FOXO DBD close to the cluster of basic residues that are known to participate in DNA binding (Figures 3c and 6) Jin and Liao, 1999;Stroud et al, 2006;Tsai et al, 2006Tsai et al, , 2007. It has therefore been suggested that phosphorylation in this basic region might inhibit FOXO binding to DNA (Zhang et al, 2002).…”

Section: Phosphorylation Of the Foxo Dbdmentioning

confidence: 98%

“…Cluster of basic residues following helix H4 in the C terminus of FOXK1a DBD interacts with nucleotides upstream from the core sequence through hydrogen bonds and bridging water molecules. In the periphery of Jin and Liao, 1999;Stroud et al, 2006;Tsai et al, 2006Tsai et al, , 2007; gray, residues of FOXO4 that were predicted to be involved in DNA binding based on homology modeling (Boura et al, 2007); brown, AKT/protein kinase B (PKB)/serum-and glucocorticoid-inducible kinase (SGK) phosphorylation sites; red, non-AKT/PKB phosphorylation sites; and green, acetylation sites. Symbol (*) means that the residues in that column are identical in all sequences in the alignment.…”

Section: Structure Of Forkhead Dna-binding Domainmentioning

confidence: 99%

Structure/function relationships underlying regulation of FOXO transcription factors

2008

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The FOXO subgroup of forkhead transcription factors plays a central role in cell-cycle control, differentiation, metabolism control, stress response and apoptosis. Therefore, the function of these important molecules is tightly controlled by a wide range of protein-protein interactions and posttranslational modifications including phosphorylation, acetylation and ubiquitination. The mechanisms by which these processes regulate FOXO activity are mostly elusive. This review focuses on recent advances in structural studies of forkhead transcription factors and the insights they provide into the mechanism of DNA recognition. On the basis of these data, we discuss structural aspects of protein-protein interactions and posttranslational modifications that target the forkhead domain and the nuclear localization signal of FOXO proteins.

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Structure of the Forkhead Domain of FOXP2 Bound to DNA

Cited by 174 publications

References 41 publications

The mutant leucine-zipper domain impairs both dimerization and suppressive function of Foxp3 in T cells

The mutant leucine-zipper domain impairs both dimerization and suppressive function of Foxp3 in T cells

Conserved forkhead dimerization motif controls DNA replication timing and spatial organization of chromosomes in S. cerevisiae

Structure/function relationships underlying regulation of FOXO transcription factors

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