Molecular Mechanism of LEDGF/p75 Dimerization

0539172 - ÚMG 2021 RIV GB eng J - Journal Article
Lux, V. - Brouns, T. - Cermakova, K. - Srb, P. - Fábry, Milan - Mádlíková, M. - Hořejší, Magdalena - Kukačka, Z. - Novák, P. - Kugler, M. - Brynda, Jiří - DeRijck, J. - Christ, F. - Debyser, Z. - Veverka, V.
Molecular Mechanism of LEDGF/p75 Dimerization.
Structure. Roč. 28, č. 12 (2020), s. 1288-1299. ISSN 0969-2126. E-ISSN 1878-4186
R&D Projects: GA MŠMT(CZ) ED1.1.00/02.0109
Institutional support: RVO:68378050
Keywords : PSIP1 * domain swapping * eletrostatic stapling * epigenetics * mixed-lineage leukemia * paramagnetic NMR * protein-protein interaction * transcription
OECD category: Biochemistry and molecular biology
Impact factor: 5.006, year: 2020
Method of publishing: Limited access
https://www.cell.com/structure/fulltext/S0969-2126(20)30325-7?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0969212620303257%3Fshowall%3Dtrue

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 a 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.
Permanent Link: http://hdl.handle.net/11104/0316873