Molecular Mechanism of LEDGF/p75 Dimerization

J 2020

Molecular Mechanism of LEDGF/p75 Dimerization

LUX, Vanda; Tine BROUNS; Katerina CERMAKOVA; Pavel SRB; Milan FABRY et al.

Základní údaje

Originální název

Molecular Mechanism of LEDGF/p75 Dimerization

Autoři

Vydání

Structure, CAMBRIDGE, CELL PRESS, 2020, 0969-2126

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10608 Biochemistry and molecular biology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 5.006

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:90043/20:00139217

Organizační jednotka

CIISB

Klíčová slova anglicky

protein-protein interaction; mixed-lineage leukemia; epigenetics; transcription; PSIP1domain swapping; eletrostatic stapling; paramagnetic NMR

Štítky

ne MU, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 28. 3. 2025 20:34, Mgr. Eva Dubská

Anotace

V originále

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.

Návaznosti

90043, velká výzkumná infrastruktura

Název: CIISB

Citovat

LUX, Vanda; Tine BROUNS; Katerina CERMAKOVA; Pavel SRB; Milan FABRY; Marcela MADLIKOVA; Magdalena HOREJSI; Zdenek KUKACKA; Petr NOVAK; Michael KUGLER; Jiri BRYNDA; Jan DERIJCK; Frauke CHRIST; Zeger DEBYSER a Vaclav VEVERKA. Molecular Mechanism of LEDGF/p75 Dimerization. Structure. CAMBRIDGE: CELL PRESS, 2020, roč. 28, č. 12, s. 1288-1306. ISSN 0969-2126. Dostupné z: https://doi.org/10.1016/j.str.2020.08.012.

@article{2487328,
   author = {Lux, Vanda and Brouns, Tine and Cermakova, Katerina and Srb, Pavel and Fabry, Milan and Madlikova, Marcela and Horejsi, Magdalena and Kukacka, Zdenek and Novak, Petr and Kugler, Michael and Brynda, Jiri and DeRijck, Jan and Christ, Frauke and Debyser, Zeger and Veverka, Vaclav},
   article_location = {CAMBRIDGE},
   article_number = {12},
   doi = {https://doi.org/10.1016/j.str.2020.08.012},
   keywords = {protein-protein interaction; mixed-lineage leukemia; epigenetics; transcription; PSIP1domain swapping; eletrostatic stapling; paramagnetic NMR},
   language = {eng},
   issn = {0969-2126},
   journal = {Structure},
   title = {Molecular Mechanism of LEDGF/p75 Dimerization},
   url = {https://www.sciencedirect.com/science/article/pii/S0969212620303257?via%3Dihub#kwrds0010},
   volume = {28},
   year = {2020}
}

TY  - JOUR
ID  - 2487328
AU  - Lux, Vanda - Brouns, Tine - Cermakova, Katerina - Srb, Pavel - Fabry, Milan - Madlikova, Marcela - Horejsi, Magdalena - Kukacka, Zdenek - Novak, Petr - Kugler, Michael - Brynda, Jiri - DeRijck, Jan - Christ, Frauke - Debyser, Zeger - Veverka, Vaclav
PY  - 2020
TI  - Molecular Mechanism of LEDGF/p75 Dimerization
JF  - Structure
VL  - 28
IS  - 12
SP  - 1288-1306
EP  - 1288-1306
PB  - CELL PRESS
SN  - 09692126
KW  - protein-protein interaction
KW  - mixed-lineage leukemia
KW  - epigenetics
KW  - transcription
KW  - PSIP1domain swapping
KW  - eletrostatic stapling
KW  - paramagnetic NMR
UR  - https://www.sciencedirect.com/science/article/pii/S0969212620303257?via%3Dihub#kwrds0010
N2  - 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.
ER  -

LUX, Vanda; Tine BROUNS; Katerina CERMAKOVA; Pavel SRB; Milan FABRY; Marcela MADLIKOVA; Magdalena HOREJSI; Zdenek KUKACKA; Petr NOVAK; Michael KUGLER; Jiri BRYNDA; Jan DERIJCK; Frauke CHRIST; Zeger DEBYSER a Vaclav VEVERKA. Molecular Mechanism of LEDGF/p75 Dimerization. \textit{Structure}. CAMBRIDGE: CELL PRESS, 2020, roč.~28, č.~12, s.~1288-1306. ISSN~0969-2126. Dostupné z: https://doi.org/10.1016/j.str.2020.08.012.

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