Multiple cellular proteins interact with LEDGF/p75 through a conserved unstructured consensus motif
Language English Country Great Britain, England Media electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
26245978
DOI
10.1038/ncomms8968
PII: ncomms8968
Knihovny.cz E-resources
- MeSH
- Dimerization MeSH
- Escherichia coli MeSH
- Histone-Lysine N-Methyltransferase metabolism MeSH
- HIV Integrase metabolism MeSH
- Consensus Sequence MeSH
- Lentivirus enzymology MeSH
- Humans MeSH
- Intercellular Signaling Peptides and Proteins metabolism MeSH
- Molecular Sequence Data MeSH
- RNA-Binding Proteins MeSH
- Proteins metabolism MeSH
- Myeloid-Lymphoid Leukemia Protein metabolism MeSH
- Repressor Proteins metabolism MeSH
- Amino Acid Sequence MeSH
- Protein Structure, Tertiary MeSH
- Transcription Factors MeSH
- Transposases metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- CDCA7L protein, human MeSH Browser
- Histone-Lysine N-Methyltransferase MeSH
- HIV Integrase MeSH
- Iws1 protein, human MeSH Browser
- KMT2A protein, human MeSH Browser
- lens epithelium-derived growth factor MeSH Browser
- Intercellular Signaling Peptides and Proteins MeSH
- POGZ protein, human MeSH Browser
- RNA-Binding Proteins MeSH
- Proteins MeSH
- Myeloid-Lymphoid Leukemia Protein MeSH
- Repressor Proteins MeSH
- Transcription Factors MeSH
- Transposases MeSH
Lens epithelium-derived growth factor (LEDGF/p75) is an epigenetic reader and attractive therapeutic target involved in HIV integration and the development of mixed lineage leukaemia (MLL1) fusion-driven leukaemia. Besides HIV integrase and the MLL1-menin complex, LEDGF/p75 interacts with various cellular proteins via its integrase binding domain (IBD). Here we present structural characterization of IBD interactions with transcriptional repressor JPO2 and domesticated transposase PogZ, and show that the PogZ interaction is nearly identical to the interaction of LEDGF/p75 with MLL1. The interaction with the IBD is maintained by an intrinsically disordered IBD-binding motif (IBM) common to all known cellular partners of LEDGF/p75. In addition, based on IBM conservation, we identify and validate IWS1 as a novel LEDGF/p75 interaction partner. Our results also reveal how HIV integrase efficiently displaces cellular binding partners from LEDGF/p75. Finally, the similar binding modes of LEDGF/p75 interaction partners represent a new challenge for the development of selective interaction inhibitors.
Institute of Molecular Genetics of the ASCR v v i Videnska 1083 142 20 Prague Czech Republic
KU Leuven Molecular Virology and Gene Therapy Kapucijnenvoer 33 B 3000 Leuven Belgium
See more in PubMed
J Mol Biol. 2002 May 24;319(1):209-27 PubMed
EMBO J. 1998 Nov 16;17(22):6723-9 PubMed
Mol Pharmacol. 2011 Feb;79(2):308-17 PubMed
PLoS Genet. 2012;8(5):e1002717 PubMed
Future Med Chem. 2014 Mar;6(4):447-62 PubMed
Mol Cell. 2010 Dec 10;40(5):725-35 PubMed
Cancer Cell. 2003 Aug;4(2):99-110 PubMed
Nucleic Acids Res. 2006 Mar 20;34(5):1653-65 PubMed
Mol Cell Biol. 2013 May;33(10):2067-77 PubMed
J Cell Sci. 2006 Jun 15;119(Pt 12):2563-71 PubMed
Cancer Cell. 2008 Jul 8;14(1):36-46 PubMed
J Mol Biol. 2007 Sep 14;372(2):407-21 PubMed
J Biomol NMR. 2006;36 Suppl 1:3 PubMed
Nucleic Acids Res. 2006 Apr 28;34(8):2219-29 PubMed
J Biol Chem. 2003 Aug 29;278(35):33528-39 PubMed
Nucleic Acids Res. 2014 Feb;42(4):2112-25 PubMed
Anal Biochem. 2006 Oct 15;357(2):289-98 PubMed
BMC Struct Biol. 2009 Apr 30;9:26 PubMed
Genes Dev. 2007 Jul 15;21(14):1767-78 PubMed
Nature. 2012 Feb 12;482(7386):542-6 PubMed
Leukemia. 2013 Jun;27(6):1245-53 PubMed
PLoS One. 2012;7(1):e30132 PubMed
Mol Cell Biol. 2006 Oct;26(19):7201-10 PubMed
J Biol Chem. 2011 Dec 2;286(48):41812-25 PubMed
Virology. 2013 Jan 5;435(1):102-9 PubMed
EMBO J. 2006 Mar 22;25(6):1324-34 PubMed
Mol Ther. 2012 Nov;20(11):2064-75 PubMed
Cancer Res. 2005 Jul 1;65(13):5607-19 PubMed
J Mol Biol. 2006 Jul 21;360(4):760-73 PubMed
J Biol Chem. 2012 May 11;287(20):16801-11 PubMed
Cancer Res. 2009 Dec 15;69(24):9306-14 PubMed
J Biomol NMR. 2004 Oct;30(2):225-6 PubMed
Semin Cell Dev Biol. 2015 Jan;37:44-55 PubMed
Cell Host Microbe. 2015 Jan 14;17(1):107-17 PubMed
J Biol Chem. 2012 Jun 15;287(25):21189-203 PubMed
PLoS Pathog. 2009 Jan;5(1):e1000259 PubMed
J Biomol NMR. 2009 Aug;44(4):213-23 PubMed
Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W362-5 PubMed
Nat Chem Biol. 2010 Jun;6(6):442-8 PubMed
J Biol Chem. 2014 Jul 25;289(30):20477-88 PubMed
J Biol Chem. 2004 Nov 19;279(47):48883-92 PubMed
Cell Death Differ. 2002 Sep;9(9):915-25 PubMed
Trends Biochem Sci. 2015 Jan;40(1):36-48 PubMed
PLoS Pathog. 2014 May 29;10(5):e1004171 PubMed
J Biol Chem. 2009 Apr 24;284(17):11467-77 PubMed
Cancer Res. 2014 Sep 15;74(18):5139-51 PubMed
J Biol Chem. 2003 Jan 3;278(1):372-81 PubMed
Invest Ophthalmol Vis Sci. 1999 Jun;40(7):1444-51 PubMed
Genes Dev. 2008 Dec 15;22(24):3422-34 PubMed
Blood. 2014 Dec 11;124(25):3730-7 PubMed
J Biol Chem. 2005 Mar 25;280(12):11552-9 PubMed
Proc Natl Acad Sci U S A. 2005 Nov 29;102(48):17308-13 PubMed
Curr Opin Chem Biol. 2013 Jun;17(3):339-45 PubMed
J Biol Chem. 2009 Nov 27;284(48):33580-99 PubMed
J Biol Chem. 2010 Jan 1;285(1):541-54 PubMed
Expert Opin Ther Pat. 2014 Jun;24(6):609-32 PubMed
Nucleic Acids Res. 2013 Apr 1;41(6):3924-36 PubMed
Nanoscale. 2014 May 7;6(9):4611-9 PubMed
Nat Med. 2005 Dec;11(12):1287-9 PubMed
Nature. 1995 Nov 30;378(6556):505-8 PubMed
Nucleic Acids Res. 2010 Oct;38(18):6135-47 PubMed
Chem Rev. 2014 Jul 9;114(13):6733-78 PubMed
Nat Cell Biol. 2010 Jul;12(7):719-27 PubMed
J Biol Chem. 2009 Nov 13;284(46):31928-35 PubMed
Nat Struct Mol Biol. 2005 Jun;12(6):526-32 PubMed
Nat Rev Cancer. 2007 Nov;7(11):823-33 PubMed
Mol Carcinog. 2014 Apr;53(4):300-13 PubMed
Retrovirology. 2013 Nov 21;10:144 PubMed
Genes Dev. 2007 Jan 15;21(2):160-74 PubMed
The Impact of Lens Epithelium-Derived Growth Factor p75 Dimerization on Its Tethering Function
Multivalency of nucleosome recognition by LEDGF
A ubiquitous disordered protein interaction module orchestrates transcription elongation
Affinity switching of the LEDGF/p75 IBD interactome is governed by kinase-dependent phosphorylation
PDB
2N3A
