期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 30, 页码 E7053-E7062出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1803909115
关键词
LEDGF/p75; disordered proteins; protein-protein interactions; phosphorylation; leukemia
资金
- KU Leuven Interdisciplinair onderzoeksprogramma (IDO) Program [IDO/12/008-3E130241]
- Czech Science Foundation [16-06357S]
- Research Foundation - Flanders [G.0595.13]
- Ministry of Education of the Czech Republic [LO1304, LM2015070, LM2015043, LK11205]
- European Regional Development Fund
- Operational Programme Research, Development and Education
- project Chemical Biology for Drugging Undruggable Targets (ChemBioDrug) [CZ.02.1.01/0.0/0.0/16_019/0000729]
- Czech Academy of Sciences [RVO61388963, RVO61388971, RVO68378050]
- Agency for Innovation by Science and Technology [SBO 140038]
- Belgian National Foundation Against Cancer
- IDO program
- KU Leuven Industrial Research Fund
- National Cancer Institute [R00CA187565]
- Cancer Prevention and Research Institute of Texas [RR170036]
- Gabrielle's Angel Foundation for Cancer Research
- NATIONAL CANCER INSTITUTE [R00CA187565] Funding Source: NIH RePORTER
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.
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