PSIP1

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 PSIP1 gene.[5][6]

PSIP1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPSIP1, DFS70, LEDGF, PAIP, PSIP2, p52, p75, PC4 and SFRS1 interacting protein 1
External IDsOMIM: 603620 MGI: 2142116 HomoloGene: 13242 GeneCards: PSIP1
Gene location (Human)
Chr.Chromosome 9 (human)[1]
Band9p22.3Start15,464,066 bp[1]
End15,510,995 bp[1]
RNA expression pattern




More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

11168

101739

Ensembl

ENSG00000164985

ENSMUSG00000028484

UniProt

O75475

Q99JF8

RefSeq (mRNA)

NM_001128217
NM_021144
NM_033222
NM_001317898
NM_001317900

NM_001290527
NM_133948
NM_001347143
NM_001355203

RefSeq (protein)

NP_001121689
NP_001304827
NP_001304829
NP_066967
NP_150091

NP_001277456
NP_001334072
NP_598709
NP_001342132

Location (UCSC)Chr 9: 15.46 – 15.51 MbChr 4: 83.46 – 83.49 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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] LEDGF/p75 recruits MLL complexes to HOX genes to regulate their expression.[12] LEDGF/p52 is shown to recruit splicing factors to H3K36 trimethylated chromatin to modulate alternative splicing,[13] also regulates HOTTIP lncRNA, which is shown to regulate HOX genes in cis.[14]

Structure

LEDGF/p75 is a 60kDa, 530-amino-acid-long protein.[15] 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,[16] 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.

Interactions

PSIP1 has been shown to interact with the proteins ASF/SF2, JPO2, Cdc7-Dbf4, and POGZ as well as the menin/MLL protein complex.[17][18]

References

  1. GRCh38: Ensembl release 89: ENSG00000164985 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000028484 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "Entrez Gene: PSIP1 PC4 and SFRS1 interacting protein 1".
  6. 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. PMID 10721720.
  7. 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. PMID 12407101.
  8. Vandekerckhove L, Christ F, Van Maele B, De Rijck J, Gijsbers R, Van den Haute C, Witvrouw M, Debyser Z (February 2006). "Transient and stable knockdown of the integrase cofactor LEDGF/p75 reveals its role in the replication cycle of human immunodeficiency virus". J. Virol. 80 (4): 1886–96. doi:10.1128/JVI.80.4.1886-1896.2006. PMC 1367129. PMID 16439544.
  9. Shun MC, Raghavendra NK, Vandegraaff N, Daigle JE, Hughes S, Kellam P, Cherepanov P, Engelman A (July 2007). "LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration". Genes Dev. 21 (14): 1767–78. doi:10.1101/gad.1565107. PMC 1920171. PMID 17639082.
  10. 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. Bibcode:2006Sci...314..461L. doi:10.1126/science.1132319. PMID 16959972. S2CID 24756699.
  11. 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. PMID 20473303.
  12. Pradeepa, Madapura M.; Grimes, Graeme R.; Taylor, Gillian C. A.; Sutherland, Heidi G.; Bickmore, Wendy A. (2014-08-18). "Psip1/Ledgf p75 restrains Hox gene expression by recruiting both trithorax and polycomb group proteins". Nucleic Acids Research. 42 (14): 9021–9032. doi:10.1093/nar/gku647. ISSN 0305-1048. PMC 4132756. PMID 25056311.
  13. Pradeepa, Madapura M.; Sutherland, Heidi G.; Ule, Jernej; Grimes, Graeme R.; Bickmore, Wendy A. (2012-05-17). "Psip1/Ledgf p52 Binds Methylated Histone H3K36 and Splicing Factors and Contributes to the Regulation of Alternative Splicing". PLOS Genetics. 8 (5): e1002717. doi:10.1371/journal.pgen.1002717. ISSN 1553-7404. PMC 3355077. PMID 22615581.
  14. Pradeepa, Madapura M.; McKenna, Fionnuala; Taylor, Gillian C. A.; Bengani, Hemant; Grimes, Graeme R.; Wood, Andrew J.; Bhatia, Shipra; Bickmore, Wendy A. (2017-04-06). "Psip1/p52 regulates posterior Hoxa genes through activation of lncRNA Hottip". PLOS Genetics. 13 (4): e1006677. doi:10.1371/journal.pgen.1006677. ISSN 1553-7404. PMC 5383017. PMID 28384324.
  15. Llano M, Morrison J, Poeschla EM (2009). "Virological and cellular roles of the transcriptional coactivator LEDGF/p75". HIV Interactions with Host Cell Proteins. Curr. Top. Microbiol. Immunol. Current Topics in Microbiology and Immunology. 339. pp. 125–46. doi:10.1007/978-3-642-02175-6_7. ISBN 978-3-642-02174-9. PMC 3093762. PMID 20012527.
  16. 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. PMID 15895093. S2CID 20898124.
  17. 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. PMID 9885563.
  18. Hughes S, Jenkins V, Dar MJ, Engelman A, Cherepanov P (January 2010). "Transcriptional co-activator LEDGF interacts with Cdc7-activator of S-phase kinase (ASK) and stimulates its enzymatic activity". J. Biol. Chem. 285 (1): 541–54. doi:10.1074/jbc.M109.036491. PMC 2804203. PMID 19864417.

Further reading

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