Molecular Mechanism of LEDGF/p75 Dimerization
| Autor: | Kateřina Čermáková, Magdalena Hořejší, Zeger Debyser, Milan Fábry, Zdeněk Kukačka, Tine Brouns, Marcela Mádlíková, M. Kugler, Frauke Christ, Pavel Srb, Vaclav Veverka, Jan DeRijck, Jiří Brynda, Vanda Lux, Petr Novák |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
musculoskeletal diseases
Dimer Static Electricity paramagnetic NMR Interactome Protein–protein interaction protein-protein interaction 03 medical and health sciences PSIP1 chemistry.chemical_compound Protein Domains eletrostatic stapling Structural Biology Transcription (biology) Humans skin and connective tissue diseases domain swapping Molecular Biology 030304 developmental biology 0303 health sciences biology epigenetics Chemistry 030302 biochemistry & molecular biology Eukaryotic transcription biological factors Integrase nervous system biology.protein Biophysics Intercellular Signaling Peptides and Proteins sense organs Protein Multimerization transcription Binding domain mixed-lineage leukemia |
| Zdroj: | Structure |
| Popis: | 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. ispartof: STRUCTURE vol:28 issue:12 pages:1288-+ ispartof: location:United States status: published |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|