Molecular Mechanism of LEDGF/p75 Dimerization

Structure. 2020 Dec 1;28(12):1288-1299.e7. doi: 10.1016/j.str.2020.08.012. Epub 2020 Sep 17.


Dimerization of many eukaryotic transcription regulatory factors is critical for their function. Regulatory role of an epigenetic reader lens epithelium-derived growth factor/p75 (LEDGF/p75) requires at least two copies of this protein to overcome the nucleosome-induced barrier to transcription elongation. Moreover, various LEDGF/p75 binding partners are enriched for dimeric features, further underscoring the functional regulatory role of LEDGF/p75 dimerization. Here, we dissected the minimal dimerization region in the C-terminal part of LEDGF/p75 and, using paramagnetic NMR spectroscopy, identified the key molecular contacts that helped to refine the solution structure of the dimer. The LEDGF/p75 dimeric assembly is stabilized by domain swapping within the integrase binding domain and additional electrostatic "stapling" of the negatively charged α helix formed in the intrinsically disordered C-terminal region. We validated the dimerization mechanism using structure-inspired dimerization defective LEDGF/p75 variants and chemical crosslinking coupled to mass spectrometry. We also show how dimerization might affect the LEDGF/p75 interactome.

Keywords: PSIP1; domain swapping; eletrostatic stapling; epigenetics; mixed-lineage leukemia; paramagnetic NMR; protein-protein interaction; transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Intercellular Signaling Peptides and Proteins / chemistry*
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Protein Domains
  • Protein Multimerization*
  • Static Electricity


  • Intercellular Signaling Peptides and Proteins
  • lens epithelium-derived growth factor