Affinity switching of the LEDGF/p75 IBD interactome is governed by kinase-dependent phosphorylation

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11310%2F18%3A10403787" target="_blank" >RIV/00216208:11310/18:10403787 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61388971:_____/18:00492184 RIV/68378050:_____/18:00495066 RIV/61388963:_____/18:00492184

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=e-iI2r9BE7" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=e-iI2r9BE7</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1073/pnas.1803909115" target="_blank" >10.1073/pnas.1803909115</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Affinity switching of the LEDGF/p75 IBD interactome is governed by kinase-dependent phosphorylation

Popis výsledku v původním jazyce

Lens epithelium-derived growth factor/p75 (LE DGF/p75, or PSIP1) is a transcriptional coactivator that tethers other proteins to gene bodies. The chromatin tethering function of LEDGF/p75 is hijacked by HIV integrase to ensure viral integration at sites of active transcription. LEDGF/p75 is also important for the development of mixed-lineage leukemia (MLL), where it tethers the MLL1 fusion complex at aberrant MLL targets, inducing malignant transformation. However, little is known about how the LEDGF/p75 protein interaction network is regulated. Here, we obtained solution structures of the complete interfaces between the LEDGF/p75 integrase binding domain (IBD) and its cellular binding partners and validated another binding partner, Mediator subunit 1 (MED1). We reveal that structurally conserved IBD-binding motifs (IBMs) on known LEDGF/ p75 binding partners can be regulated by phosphorylation, permitting switching between low- and high-affinity states. Finally, we show that elimination of IBM phosphorylation sites on MLL1 disrupts the oncogenic potential of primary MLL1-rearranged leukemic cells. Our results demonstrate that kinase-dependent phosphorylation of MLL1 represents a previously unknown oncogenic dependency that may be harnessed in the treatment of MLL-rearranged leukemia.

Název v anglickém jazyce

Affinity switching of the LEDGF/p75 IBD interactome is governed by kinase-dependent phosphorylation

Popis výsledku anglicky

Lens epithelium-derived growth factor/p75 (LE DGF/p75, or PSIP1) is a transcriptional coactivator that tethers other proteins to gene bodies. The chromatin tethering function of LEDGF/p75 is hijacked by HIV integrase to ensure viral integration at sites of active transcription. LEDGF/p75 is also important for the development of mixed-lineage leukemia (MLL), where it tethers the MLL1 fusion complex at aberrant MLL targets, inducing malignant transformation. However, little is known about how the LEDGF/p75 protein interaction network is regulated. Here, we obtained solution structures of the complete interfaces between the LEDGF/p75 integrase binding domain (IBD) and its cellular binding partners and validated another binding partner, Mediator subunit 1 (MED1). We reveal that structurally conserved IBD-binding motifs (IBMs) on known LEDGF/ p75 binding partners can be regulated by phosphorylation, permitting switching between low- and high-affinity states. Finally, we show that elimination of IBM phosphorylation sites on MLL1 disrupts the oncogenic potential of primary MLL1-rearranged leukemic cells. Our results demonstrate that kinase-dependent phosphorylation of MLL1 represents a previously unknown oncogenic dependency that may be harnessed in the treatment of MLL-rearranged leukemia.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10601 - Cell biology

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Proceedings of the National Academy of Sciences of the United States of America

ISSN

0027-8424

e-ISSN

—

Svazek periodika

115

Číslo periodika v rámci svazku

30

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

10

Strana od-do

"E7053"-"E7062"

Kód UT WoS článku

000439574700012

EID výsledku v databázi Scopus

2-s2.0-85052021815