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PSIP1

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; OMA:PSIP1 - orthologs
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: 83.37 – 83.4 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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]

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. ^ a b c GRCh38: Ensembl release 89: ENSG00000164985 – Ensembl, May 2017
  2. ^ a b c 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. S2CID 37421436.
  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. Current Topics in Microbiology and Immunology. Vol. 339. pp. 125–46. doi:10.1007/978-3-642-02175-6_7. ISBN 978-3-642-02174-9. PMC 3093762. PMID 20012527. {{cite book}}: |journal= ignored (help)
  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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