< Back to previous page

Publication

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

Journal Contribution - Journal Article

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.
Journal: Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
Issue: 30
Volume: 115
Pages: E7053 - E7062
Number of pages: 10
Publication year:2018
BOF-keylabel:yes
IOF-keylabel:yes
BOF-publication weight:6
CSS-citation score:1
Authors:International
Authors from:Higher Education
Accessibility:Open