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Edited by Roeland Nusse, Stanford University School of Medicine, Stanford, CA, and approved December 10, 2019 (received for review August 15, 2019)
Significance
Transcription factors bound to enhancers that are distant from target genes control gene transcription to regulate many biological processes. LDB1/SSBP complexes function as a common core of diverse important protein complexes that are known to be critical for development and can connect enhancers and genes. SSBPs stabilize these complexes by preventing LDB1 degradation by the 26S proteasome. Here we provide a glimpse of the structure of the human core LDB1/SSBP2 protein complex and how it may be regulated.
Abstract
The Lim domain binding proteins (LDB1 and LDB2 in human and Chip in Drosophila) play critical roles in cell fate decisions through partnership with multiple Lim-homeobox and Lim-only proteins in diverse developmental systems including cardiogenesis, neurogenesis, and hematopoiesis. In mammalian erythroid cells, LDB1 dimerization supports long-range connections between enhancers and genes involved in erythropoiesis, including the β-globin genes. Single-stranded DNA binding proteins (SSBPs) interact specifically with the LDB/Chip conserved domain (LCCD) of LDB proteins and stabilize LDBs by preventing their proteasomal degradation, thus promoting their functions in gene regulation. The structural basis for LDB1 self-interaction and interface with SSBPs is unclear. Here we report a crystal structure of the human LDB1/SSBP2 complex at 2.8-Å resolution. The LDB1 dimerization domain (DD) contains an N-terminal nuclear transport factor 2 (NTF2)-like subdomain and a small helix 4–helix 5 subdomain, which together form the LDB1 dimerization interface. The 2 LCCDs in the symmetric LDB1 dimer flank the core DDs, with each LCCD forming extensive interactions with an SSBP2 dimer. The conserved linker between LDB1 DD and LCCD covers a potential ligand-binding pocket of the LDB1 NTF2-like subdomain and may serve as a regulatory site for LDB1 structure and function. Our structural and biochemical data provide a much-anticipated structural basis for understanding how LDB1 and the LDB1/SSBP interactions form the structural core of diverse complexes mediating cell choice decisions and long-range enhancer–promoter interactions.
- LIM domain binding protein 1 (LDB1)
- single-stranded DNA binding protein 2 (SSBP2)
- dimerization
- crystal structure
- Wnt enhanceosome
Footnotes
- ↵1To whom correspondence may be addressed. Email: xuwq2{at}shanghaitech.edu.cn, snow{at}ibp.ac.cn, or ann.dean{at}nih.gov.
Author contributions: X.-X.Y., A.D., and W.X. designed research; H.W., J.K., Z.W., and X.-X.Y. performed research; H.W., J.K., Z.W., X.-X.Y., A.D., and W.X. analyzed data; and H.W., A.D., and W.X. wrote the paper.
The authors declare no competing interest.
This article is a PNAS Direct Submission.
Data deposition: The atomic coordinates and structure factors of the LDB1/SSBP2 complex have been deposited in the Protein Data Bank, https://www.rcsb.org/ under the accession code 6TYD.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1914181117/-/DCSupplemental.
Published under the PNAS license.
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Crystal structure of human LDB1 in complex with SSBP2
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- Biological Sciences
- Biophysics and Computational Biology
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