Affinity switching of the LEDGF/p75 IBD interactome is governed by kinase-dependent phosphorylation
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F18%3A00492184" target="_blank" >RIV/61388963:_____/18:00492184 - isvavai.cz</a>
Alternative codes found
RIV/61388971:_____/18:00492184 RIV/68378050:_____/18:00495066 RIV/00216208:11310/18:10403787
Result on the web
<a href="http://dx.doi.org/10.1073/pnas.1803909115" target="_blank" >http://dx.doi.org/10.1073/pnas.1803909115</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1073/pnas.1803909115" target="_blank" >10.1073/pnas.1803909115</a>
Alternative languages
Result language
angličtina
Original language name
Affinity switching of the LEDGF/p75 IBD interactome is governed by kinase-dependent phosphorylation
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2018
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Proceedings of the National Academy of Sciences of the United States of America
ISSN
0027-8424
e-ISSN
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Volume of the periodical
115
Issue of the periodical within the volume
30
Country of publishing house
US - UNITED STATES
Number of pages
10
Pages from-to
"E7053"-"E7062"
UT code for WoS article
000439574700012
EID of the result in the Scopus database
2-s2.0-85052021815