5YI9

Solution structure of the LEDGF/p75 IBD - JPO2 (aa 56-91) complex

5YI9 の概要

• エントリーDOI: 10.2210/pdb5yi9/pdb
• 分子名称: PC4 and SFRS1-interacting protein,Cell division cycle-associated 7-like protein (1 entity in total)
• 機能のキーワード: protein-protein complex, epigenetics, leukemia, transcription
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 16338.52

構造登録者

Veverka, V. (登録日: 2017-10-03, 公開日: 2018-08-15, 最終更新日: 2024-05-15)

主引用文献

Sharma, S.,Cermakova, K.,De Rijck, J.,Demeulemeester, J.,Fabry, M.,El Ashkar, S.,Van Belle, S.,Lepsik, M.,Tesina, P.,Duchoslav, V.,Novak, P.,Hubalek, M.,Srb, P.,Christ, F.,Rezacova, P.,Hodges, H.C.,Debyser, Z.,Veverka, V.
Affinity switching of the LEDGF/p75 IBD interactome is governed by kinase-dependent phosphorylation.
Proc. Natl. Acad. Sci. U.S.A., 115:E7053-E7062, 2018

PubMed Abstract: Lens epithelium-derived growth factor/p75 (LEDGF/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.

PubMed: 29997176
DOI: 10.1073/pnas.1803909115

実験手法

SOLUTION NMR