Pradeepa, M. M., Sutherland, H. G., Ule, J., Grimes, G. R. & Bickmore, W. A. Psip1/Ledgf p52 binds methylated histone H3K36 and splicing factors and contributes to the regulation of alternative splicing. PLoS. Genet. 8, e1002717 (2012).
Eidahl, J. O. et al. Structural basis for high-affinity binding of LEDGF PWWP to mononucleosomes. Nucleic Acids Res. 41, 3924–3936 (2013).
Sutherland, H. G. et al. Disruption of Ledgf/Psip1 results in perinatal mortality and homeotic skeletal transformations. Mol. Cell Biol. 26, 7201–7210 (2006).
Yu, B. D., Hess, J. L., Horning, S. E., Brown, G. A. & Korsmeyer, S. J. Altered Hox expression and segmental identity in Mll-mutant mice. Nature 378, 505–508 (1995).
Ling, Y., Smith, A. J. & Morgan, G. T. A sequence motif conserved in diverse nuclear proteins identifies a protein interaction domain utilised for nuclear targeting by human TFIIS. Nucleic Acids Res. 34, 2219–2229 (2006).
Ge, H., Si, Y. & Roeder, R. G. Isolation of cDNAs encoding novel transcription coactivators p52 and p75 reveals an alternate regulatory mechanism of transcriptional activation. EMBO J 17, 6723–6729 (1998).
Wu, X., Daniels, T., Molinaro, C., Lilly, M. B. & Casiano, C. A. Caspase cleavage of the nuclear autoantigen LEDGF/p75 abrogates its pro-survival function: implications for autoimmunity in atopic disorders. Cell Death Differ. 9, 915–925 (2002).
Singh, D. P., Ohguro, N., Chylack, L. T. Jr. & Shinohara, T. Lens epithelium-derived growth factor: increased resistance to thermal and oxidative stresses. Invest. Ophthalmol. Vis. Sci. 40, 1444–1451 (1999).
Sapoznik, S. et al. Gonadotropin-regulated lymphangiogenesis in ovarian cancer is mediated by LEDGF-induced expression of VEGF-C. Cancer Res. 69, 9306–9314 (2009).
Basu, A. et al. Expression of the stress response oncoprotein LEDGF/p75 in human cancer: a study of 21 tumor types. PLoS ONE 7, e30132 (2012).
Xu, X. et al. Human MCS5A1 candidate breast cancer susceptibility gene FBXO10 is induced by cellular stress and correlated with lens epithelium-derived growth factor (LEDGF). Mol. Carcinog. 53, 300–313 (2012).
Krivtsov, A. V. & Armstrong, S. A. MLL translocations, histone modifications and leukaemia stem-cell development. Nat. Rev. Cancer 7, 823–833 (2007).
Huang, J. et al. The same pocket in menin binds both MLL and JUND but has opposite effects on transcription. Nature 482, 542–546 (2012).
Cermakova, K. et al. Validation and Structural Characterisation of the LEDGF/p75-MLL Interface as a New Target for the Treatment of MLL-Dependent Leukaemia. Cancer Res. 74, 5139–5151 (2014).
Murai, M. J. et al. The same site on the integrase-binding domain of lens epithelium-derived growth factor is a therapeutic target for MLL leukemia and HIV. Blood 124, 3730–3737 (2014).
Cherepanov, P. et al. HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells. J. Biol. Chem. 278, 372–381 (2003).
De Rijck, J., Bartholomeeusen, K., Ceulemans, H., Debyser, Z. & Gijsbers, R. High-resolution profiling of the LEDGF/p75 chromatin interaction in the ENCODE region. Nucleic Acids Res. 38, 6135–6147 (2010).
Gijsbers, R. et al. Role of the PWWP domain of lens epithelium-derived growth factor (LEDGF)/p75 cofactor in lentiviral integration targeting. J. Biol. Chem. 286, 41812–41825 (2011).
Cherepanov, P. et al. Solution structure of the HIV-1 integrase-binding domain in LEDGF/p75. Nat. Struct. Mol. Biol. 12, 526–532 (2005).
Shun, M. C. et al. LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration. Genes Dev. 21, 1767–1778 (2007).
Ciuffi, A. et al. A role for LEDGF/p75 in targeting HIV DNA integration. Nat. Med. 11, 1287–1289 (2005).
Christ, F. et al. Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication. Nat. Chem. Biol. 6, 442–448 (2010).
Kessl, J. J. et al. Multimode, cooperative mechanism of action of allosteric HIV-1 integrase inhibitors. J. Biol. Chem. 287, 16801–16811 (2012).
Le Rouzic, E. et al. Dual inhibition of HIV-1 replication by integrase-LEDGF allosteric inhibitors is predominant at the post-integration stage. Retrovirology 10, 144 (2013).
Tsiang, M. et al. New class of HIV-1 integrase (IN) inhibitors with a dual mode of action. J. Biol. Chem. 287, 21189–21203 (2012).
Sharma, A. et al. A new class of multimerization selective inhibitors of HIV-1 integrase. PLoS Pathog. 10, e1004171 (2014).
Gupta, K. et al. Allosteric inhibition of human immunodeficiency virus integrase: late block during viral replication and abnormal multimerization involving specific protein domains. J. Biol. Chem. 289, 20477–20488 (2014).
Demeulemeester, J. et al. LEDGINs, non-catalytic site inhibitors of HIV-1 integrase: a patent review (2006–2014). Expert Opin. Ther. Pat. 24, 609–632 (2014).
Engelman, A., Kessl, J. J. & Kvaratskhelia, M. Allosteric inhibition of HIV-1 integrase activity. Curr. Opin. Chem. Biol. 17, 339–345 (2013).
Bartholomeeusen, K. et al. Differential interaction of HIV-1 integrase and JPO2 with the C terminus of LEDGF/p75. J. Mol. Biol. 372, 407–421 (2007).
Bartholomeeusen, K. et al. Lens epithelium-derived growth factor/p75 interacts with the transposase-derived DDE domain of PogZ. J. Biol. Chem. 284, 11467–11477 (2009).
Hughes, S., Jenkins, V., Dar, M. J., Engelman, A. & Cherepanov, P. Transcriptional co-activator LEDGF interacts with Cdc7-activator of S-phase kinase (ASK) and stimulates its enzymatic activity. J. Biol. Chem. 285, 541–554 (2010).
Maertens, G. N., Cherepanov, P. & Engelman, A. Transcriptional co-activator p75 binds and tethers the Myc-interacting protein JPO2 to chromatin. J. Cell Sci. 119, 2563–2571 (2006).
Huang, A. et al. Identification of a novel c-Myc protein interactor, JPO2, with transforming activity in medulloblastoma cells. Cancer Res. 65, 5607–5619 (2005).
Chen, K., Ou, X. M., Chen, G., Choi, S. H. & Shih, J. C. R1, a novel repressor of the human monoamine oxidase A. J. Biol. Chem. 280, 11552–11559 (2005).
Chen, K., Ou, X. M., Wu, J. B. & Shih, J. C. Transcription factor E2F-associated phosphoprotein (EAPP), RAM2/CDCA7L/JPO2 (R1), and simian virus 40 promoter factor 1 (Sp1) cooperatively regulate glucocorticoid activation of monoamine oxidase B. Mol. Pharmacol. 79, 308–317 (2011).
Nozawa, R. S. et al. Human POGZ modulates dissociation of HP1alpha from mitotic chromosome arms through Aurora B activation. Nat. Cell Biol. 12, 719–727 (2010).
Cherepanov, P., Ambrosio, A. L., Rahman, S., Ellenberger, T. & Engelman, A. Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75. Proc. Natl Acad. Sci. USA 102, 17308–17313 (2005).
Richardson, J. M. et al. Mechanism of Mos1 transposition: insights from structural analysis. EMBO J 25, 1324–1334 (2006).
de Castro, E. et al. ScanProsite: detection of PROSITE signature matches and ProRule-associated functional and structural residues in proteins. Nucleic Acids Res. 34, W362–W365 (2006).
van Nuland, R. et al. Quantitative dissection and stoichiometry determination of the human SET1/MLL histone methyltransferase complexes. Mol. Cell Biol. 33, 2067–2077 (2013).
Yoh, S. M., Cho, H., Pickle, L., Evans, R. M. & Jones, K. A. The Spt6 SH2 domain binds Ser2-P RNAPII to direct Iws1-dependent mRNA splicing and export. Genes Dev. 21, 160–174 (2007).
Yoh, S. M., Lucas, J. S. & Jones, K. A. The Iws1:Spt6:CTD complex controls cotranscriptional mRNA biosynthesis and HYPB/Setd2-mediated histone H3K36 methylation. Genes Dev. 22, 3422–3434 (2008).
Tsiang, M. et al. Affinities between the binding partners of the HIV-1 integrase dimer-lens epithelium-derived growth factor (IN dimer-LEDGF) complex. J. Biol. Chem. 284, 33580–33599 (2009).
Maertens, G. et al. LEDGF/p75 is essential for nuclear and chromosomal targeting of HIV-1 integrase in human cells. J. Biol. Chem. 278, 33528–33539 (2003).
Gerard, A. et al. The integrase cofactor LEDGF/p75 associates with Iws1 and Spt6 for postintegration silencing of HIV-1 gene expression in latently infected cells. Cell Host Microbe 17, 107–117 (2015).
McDonald, S. M., Close, D., Xin, H., Formosa, T. & Hill, C. P. Structure and biological importance of the Spn1-Spt6 interaction, and its regulatory role in nucleosome binding. Mol. Cell 40, 725–735 (2010).
Hare, S. et al. A novel co-crystal structure affords the design of gain-of-function lentiviral integrase mutants in the presence of modified PSIP1/LEDGF/p75. PLoS Pathog 5, e1000259 (2009).
Cherepanov, P., Devroe, E., Silver, P. A. & Engelman, A. Identification of an evolutionarily conserved domain in human lens epithelium-derived growth factor/transcriptional co-activator p75 (LEDGF/p75) that binds HIV-1 integrase. J. Biol. Chem. 279, 48883–48892 (2004).
Llano, M. et al. Identification and characterization of the chromatin-binding domains of the HIV-1 integrase interactor LEDGF/p75. J. Mol. Biol. 360, 760–773 (2006).
Turlure, F., Maertens, G., Rahman, S., Cherepanov, P. & Engelman, A. A tripartite DNA-binding element, comprised of the nuclear localization signal and two AT-hook motifs, mediates the association of LEDGF/p75 with chromatin in vivo. Nucleic Acids Res. 34, 1653–1665 (2006).
Yokoyama, A. & Cleary, M. L. Menin critically links MLL proteins with LEDGF on cancer-associated target genes. Cancer Cell 14, 36–46 (2008).
Mereau, H. et al. Impairing MLL-fusion gene-mediated transformation by dissecting critical interactions with the lens epithelium-derived growth factor (LEDGF/p75). Leukemia 27, 1245–1253 (2013).
Christ, F. & Debyser, Z. The LEDGF/p75 integrase interaction, a novel target for anti-HIV therapy. Virology 435, 102–109 (2013).
Van Roey, K. et al. Short linear motifs: ubiquitous and functionally diverse protein interaction modules directing cell regulation. Chem. Rev. 114, 6733–6778 (2014).
Via, A., Uyar, B., Brun, C. & Zanzoni, A. How pathogens use linear motifs to perturb host cell networks. Trends Biochem. Sci. 40, 36–48 (2015).
Vanderlinden, W., Lipfert, J., Demeulemeester, J., Debyser, Z. & De Feyter, S. Structure, mechanics, and binding mode heterogeneity of LEDGF/p75-DNA nucleoprotein complexes revealed by scanning force microscopy. Nanoscale 6, 4611–4619 (2014).
So, C. W., Lin, M., Ayton, P. M., Chen, E. H. & Cleary, M. L. Dimerization contributes to oncogenic activation of MLL chimeras in acute leukemias. Cancer Cell 4, 99–110 (2003).
Dunker, A. K., Bondos, S. E., Huang, F. & Oldfield, C. J. Intrinsically disordered proteins and multicellular organisms. Semin. Cell Dev. Biol. 37, 44–55 (2014).
Fukuchi, S., Homma, K., Minezaki, Y., Gojobori, T. & Nishikawa, K. Development of an accurate classification system of proteins into structured and unstructured regions that uncovers novel structural domains: its application to human transcription factors. BMC Struct. Biol. 9, 26 (2009).
Cierpicki, T. & Grembecka, J. Challenges and opportunities in targeting the menin-MLL interaction. Future Med. Chem. 6, 447–462 (2014).
Desimmie, B. A. et al. Phage display-directed discovery of LEDGF/p75 binding cyclic peptide inhibitors of HIV replication. Mol. Ther. 20, 2064–2075 (2012).
Thakur, J. K., Yadav, A. & Yadav, G. Molecular recognition by the KIX domain and its role in gene regulation. Nucleic Acids Res. 42, 2112–2125 (2014).
Ericsson, U. B., Hallberg, B. M., Detitta, G. T., Dekker, N. & Nordlund, P. Thermofluor-based high-throughput stability optimization of proteins for structural studies. Anal. Biochem. 357, 289–298 (2006).
Renshaw, P. S. et al. Sequence-specific assignment and secondary structure determination of the 195-residue complex formed by the Mycobacterium tuberculosis proteins CFP-10 and ESAT-6. J. Biomol. NMR 30, 225–226 (2004).
Veverka, V. et al. NMR assignment of the mTOR domain responsible for rapamycin binding. J. Biomol. NMR 36, (Suppl 1): 3 (2006).
Wilkinson, I. C. et al. High resolution NMR-based model for the structure of a scFv-IL-1beta complex: potential for NMR as a key tool in therapeutic antibody design and development. J. Biol. Chem. 284, 31928–31935 (2009).
Herrmann, T., Guntert, P. & Wuthrich, K. Protein NMR structure determination with automated NOE assignment using the new software CANDID and the torsion angle dynamics algorithm DYANA. J. Mol. Biol. 319, 209–227 (2002).
Shen, Y., Delaglio, F., Cornilescu, G. & Bax, A. TALOS+: a hybrid method for predicting protein backbone torsion angles from NMR chemical shifts. J. Biomol. NMR 44, 213–223 (2009).