6lbm

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Crystal Structure of FOXC2-DBD bound to a palindromic DNA sequence

Structural highlights

6lbm is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.841Å
Ligands:MG
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

FOXC2_HUMAN Defects in FOXC2 are the cause of lymphedema hereditary type 2 (LMPH2) [MIM:153200; also known as Meige lymphedema. Hereditary lymphedema is a chronic disabling condition which results in swelling of the extremities due to altered lymphatic flow. Patients with lymphedema suffer from recurrent local infections, and physical impairment.[1] Defects in FOXC2 are a cause of lymphedema-yellow nails (LYYN) [MIM:153300. LYYN is characterized by yellow, dystrophic, thick and slowly growing nails, associated with lymphedema and respiratory involvement. Lymphedema occurs more often in the lower limbs. It can appear at birth or later in life. Onset generally follows the onset of ungual abnormalities. Defects in FOXC2 are a cause of lymphedema-distichiasis (LYD) [MIM:153400. LYD is characterized by primary limb lymphedema usually starting at puberty (but in some cases later or at birth) and associated with distichiasis (double rows of eyelashes, with extra eyelashes growing from the Meibomian gland orifices).[2]

Function

FOXC2_HUMAN Transcriptional activator. Might be involved in the formation of special mesenchymal tissues.[3]

Publication Abstract from PubMed

Forkhead transcription factors bind a canonical consensus DNA motif, RYAAAYA (R = A/G, Y = C/T), as a monomer. However, the molecular mechanisms by which forkhead transcription factors bind DNA as a dimer are not well understood. In this study, we show that FOXO1 recognizes a palindromic DNA element DIV2, and mediates transcriptional regulation. The crystal structure of FOXO1/DIV2 reveals that the FOXO1 DNA binding domain (DBD) binds the DIV2 site as a homodimer. The wing1 region of FOXO1 mediates the dimerization, which enhances FOXO1 DNA binding affinity and complex stability. Further biochemical assays show that FOXO3, FOXM1 and FOXI1 also bind the DIV2 site as homodimer, while FOXC2 can only bind this site as a monomer. Our structural, biochemical and bioinformatics analyses not only provide a novel mechanism by which FOXO1 binds DNA as a homodimer, but also shed light on the target selection of forkhead transcription factors.

Mechanism of forkhead transcription factors binding to a novel palindromic DNA site.,Li J, Dai S, Chen X, Liang X, Qu L, Jiang L, Guo M, Zhou Z, Wei H, Zhang H, Chen Z, Chen L, Chen Y Nucleic Acids Res. 2021 Apr 6;49(6):3573-3583. doi: 10.1093/nar/gkab086. PMID:33577686[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
6 reviews cite this structure
Redox signaling at the crossroads of human health and disease.
Zuo et al. (2022)
5 more
11 other articles
No citations found

See Also

References

  1. ↑ Fang J, Dagenais SL, Erickson RP, Arlt MF, Glynn MW, Gorski JL, Seaver LH, Glover TW. Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome. Am J Hum Genet. 2000 Dec;67(6):1382-8. Epub 2000 Nov 8. PMID:11078474 doi:S0002-9297(07)63207-8
  2. ↑ Bell R, Brice G, Child AH, Murday VA, Mansour S, Sandy CJ, Collin JR, Brady AF, Callen DF, Burnand K, Mortimer P, Jeffery S. Analysis of lymphoedema-distichiasis families for FOXC2 mutations reveals small insertions and deletions throughout the gene. Hum Genet. 2001 Jun;108(6):546-51. PMID:11499682
  3. ↑ Miura N, Iida K, Kakinuma H, Yang XL, Sugiyama T. Isolation of the mouse (MFH-1) and human (FKHL 14) mesenchyme fork head-1 genes reveals conservation of their gene and protein structures. Genomics. 1997 May 1;41(3):489-92. PMID:9169153 doi:S0888-7543(97)94695-4
  4. ↑ Li J, Dai S, Chen X, Liang X, Qu L, Jiang L, Guo M, Zhou Z, Wei H, Zhang H, Chen Z, Chen L, Chen Y. Mechanism of forkhead transcription factors binding to a novel palindromic DNA site. Nucleic Acids Res. 2021 Apr 6;49(6):3573-3583. PMID:33577686 doi:10.1093/nar/gkab086

Contents


PDB ID 6lbm

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OCA

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