PC4 and SFRS1 interacting protein 1, also known as lens epithelium-derived growth factor (LEDGF/p75), dense fine speckles 70kD protein (DFS 70) or transcriptional coactivator p75/p52, is a protein that in humans is encoded by the PSIP1gene.[5][6]
Function
PSIP1 has not been clearly linked to a specific cellular mechanism. The term LEDGF/p75 (Lens epithelium-derived growth factor) has entered common usage based on the initial characterization of PSIP1, however this is a misnomer, as the protein is present in most tissues and has no direct role in the development of lens epithelium. LEDGF/p75, a transcription coactivator, gained prominence as a host factor that assists HIV integration[7] and is probably the only integrase interactor whose knock-down severely affects the HIV integration levels.[8][9][10] The interaction between HIV integrase and human LEDGF/p75 is a promising target for anti-HIV drug discovery.[11]
Structure
LEDGF/p75 is a 60kDa, 530-amino-acid-long protein.[12] The N-terminal portion of the protein consists of a PWWP domain, a nuclear localization sequence, and two copies of the AT-hook DNA binding motif. The C-terminal portion of LEDGF/p75 contains a structure termed the integrase-binding domain,[13] which interacts with lentiviral integrase proteins as well as numerous cellular proteins. The N-terminal portion interacts strongly with chromatin, making LEDGF/p75 a constitutively nuclear protein. An isoform of the protein, LEDGF/p52, is produced by alternative splicing. LEDGF/p52 shares the N-terminal 325 amino acids of LEDGF/p75 but lacks the integrase-binding domain.
^Singh DP, Kimura A, Chylack LT, Shinohara T (January 2000). "Lens epithelium-derived growth factor (LEDGF/p75) and p52 are derived from a single gene by alternative splicing". Gene. 242 (1–2): 265–73. doi:10.1016/S0378-1119(99)00506-5. PMID10721720.
^Cherepanov P, Maertens G, Proost P, Devreese B, Van Beeumen J, Engelborghs Y, De Clercq E, Debyser Z (January 2003). "HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells". J. Biol. Chem. 278 (1): 372–81. doi:10.1074/jbc.M209278200. PMID12407101.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^Llano M, Saenz DT, Meehan A, Wongthida P, Peretz M, Walker WH, Teo W, Poeschla EM (October 2006). "An essential role for LEDGF/p75 in HIV integration". Science. 314 (5798): 461–4. doi:10.1126/science.1132319. PMID16959972.
^Christ F, Voet A, Marchand A, Nicolet S, Desimmie BA, Marchand D, Bardiot D, Van der Veken NJ, Van Remoortel B, Strelkov SV, De Maeyer M, Chaltin P, Debyser Z (June 2010). "Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication". Nat. Chem. Biol. 6 (6): 442–8. doi:10.1038/nchembio.370. PMID20473303.
^Cherepanov P, Sun ZY, Rahman S, Maertens G, Wagner G, Engelman A (June 2005). "Solution structure of the HIV-1 integrase-binding domain in LEDGF/p75". Nat. Struct. Mol. Biol. 12 (6): 526–32. doi:10.1038/nsmb937. PMID15895093.
^Ge H, Si Y, Wolffe AP (December 1998). "A novel transcriptional coactivator, p52, functionally interacts with the essential splicing factor ASF/SF2". Mol. Cell. 2 (6): 751–9. doi:10.1016/S1097-2765(00)80290-7. PMID9885563.
Van Maele B, Debyser Z (2005). "HIV-1 integration: an interplay between HIV-1 integrase, cellular and viral proteins". AIDS Rev. 7 (1): 26–43. PMID15875659.
Van Maele B, Busschots K, Vandekerckhove L, Christ F, Debyser Z (2006). "Cellular co-factors of HIV-1 integration". Trends Biochem. Sci. 31 (2): 98–105. doi:10.1016/j.tibs.2005.12.002. PMID16403635.
Ge H, Si Y, Wolffe AP (1998). "A novel transcriptional coactivator, p52, functionally interacts with the essential splicing factor ASF/SF2". Mol. Cell. 2 (6): 751–9. doi:10.1016/S1097-2765(00)80290-7. PMID9885563.
Singh DP, Ohguro N, Kikuchi T, Sueno T, Reddy VN, Yuge K, Chylack LT, Shinohara T (2000). "Lens epithelium-derived growth factor: effects on growth and survival of lens epithelial cells, keratinocytes, and fibroblasts". Biochem. Biophys. Res. Commun. 267 (1): 373–81. doi:10.1006/bbrc.1999.1979. PMID10623627.
Singh DP, Kimura A, Chylack LT, Shinohara T (2000). "Lens epithelium-derived growth factor (LEDGF/p75) and p52 are derived from a single gene by alternative splicing". Gene. 242 (1–2): 265–73. doi:10.1016/S0378-1119(99)00506-5. PMID10721720.
Ochs RL, Muro Y, Si Y, Ge H, Chan EK, Tan EM (2000). "Autoantibodies to DFS 70 kd/transcription coactivator p75 in atopic dermatitis and other conditions". J. Allergy Clin. Immunol. 105 (6 Pt 1): 1211–20. doi:10.1067/mai.2000.107039. PMID10856157.
Kubo E, Fatma N, Sharma P, Shinohara T, Chylack LT, Akagi Y, Singh DP (2002). "Transactivation of involucrin, a marker of differentiation in keratinocytes, by lens epithelium-derived growth factor (LEDGF)". J. Mol. Biol. 320 (5): 1053–63. doi:10.1016/S0022-2836(02)00551-X. PMID12126624.
Wu X, Daniels T, Molinaro C, Lilly MB, Casiano CA (2002). "Caspase cleavage of the nuclear autoantigen LEDGF/p75 abrogates its pro-survival function: implications for autoimmunity in atopic disorders". Cell Death Differ. 9 (9): 915–25. doi:10.1038/sj.cdd.4401063. PMID12181742.
Cherepanov P, Maertens G, Proost P, Devreese B, Van Beeumen J, Engelborghs Y, De Clercq E, Debyser Z (2003). "HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells". J. Biol. Chem. 278 (1): 372–81. doi:10.1074/jbc.M209278200. PMID12407101.{{cite journal}}: CS1 maint: unflagged free DOI (link)
Maertens G, Cherepanov P, Pluymers W, Busschots K, De Clercq E, Debyser Z, Engelborghs Y (2003). "LEDGF/p75 is essential for nuclear and chromosomal targeting of HIV-1 integrase in human cells". J. Biol. Chem. 278 (35): 33528–39. doi:10.1074/jbc.M303594200. PMID12796494.{{cite journal}}: CS1 maint: unflagged free DOI (link)
Maertens G, Cherepanov P, Debyser Z, Engelborghs Y, Engelman A (2004). "Identification and characterization of a functional nuclear localization signal in the HIV-1 integrase interactor LEDGF/p75". J. Biol. Chem. 279 (32): 33421–9. doi:10.1074/jbc.M404700200. PMID15163664.{{cite journal}}: CS1 maint: unflagged free DOI (link)
Cherepanov P, Devroe E, Silver PA, Engelman A (2004). "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 (47): 48883–92. doi:10.1074/jbc.M406307200. PMID15371438.{{cite journal}}: CS1 maint: unflagged free DOI (link)
Llano M, Delgado S, Vanegas M, Poeschla EM (2004). "Lens epithelium-derived growth factor/p75 prevents proteasomal degradation of HIV-1 integrase". J. Biol. Chem. 279 (53): 55570–7. doi:10.1074/jbc.M408508200. PMID15475359.{{cite journal}}: CS1 maint: unflagged free DOI (link)
Ogawa Y, Sugiura K, Watanabe A, Kunimatsu M, Mishima M, Tomita Y, Muro Y (2004). "Autoantigenicity of DFS70 is restricted to the conformational epitope of C-terminal alpha-helical domain". J. Autoimmun. 23 (3): 221–31. doi:10.1016/j.jaut.2004.07.003. PMID15501393.
Okamoto M, Ogawa Y, Watanabe A, Sugiura K, Shimomura Y, Aoki N, Nagasaka T, Tomita Y, Muro Y (2004). "Autoantibodies to DFS70/LEDGF are increased in alopecia areata patients". J. Autoimmun. 23 (3): 257–66. doi:10.1016/j.jaut.2004.07.004. PMID15501396.
