Biology:PSIP1

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Short description: Protein found in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[1][2]

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[3] and is probably the only integrase interactor whose knock-down severely affects the HIV integration levels.[4][5][6] The interaction between HIV integrase and human LEDGF/p75 is a promising target for anti-HIV drug discovery.[7] LEDGF/p75 recruits MLL complexes to HOX genes to regulate their expression.[8] LEDGF/p52 is shown to recruit splicing factors to H3K36 trimethylated chromatin to modulate alternative splicing,[9] also regulates HOTTIP lncRNA, which is shown to regulate HOX genes in cis.[10]

Structure

LEDGF/p75 is a 60kDa, 530-amino-acid-long protein.[11] 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,[12] 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.[13][14]

References

  1. ↑ "Entrez Gene: PSIP1 PC4 and SFRS1 interacting protein 1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=11168. 
  2. ↑ "Lens epithelium-derived growth factor (LEDGF/p75) and p52 are derived from a single gene by alternative splicing". Gene 242 (1–2): 265–73. January 2000. doi:10.1016/S0378-1119(99)00506-5. PMID 10721720. 
  3. ↑ "HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells". J. Biol. Chem. 278 (1): 372–81. January 2003. doi:10.1074/jbc.M209278200. PMID 12407101. 
  4. ↑ "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. February 2006. doi:10.1128/JVI.80.4.1886-1896.2006. PMID 16439544. 
  5. ↑ "LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration". Genes Dev. 21 (14): 1767–78. July 2007. doi:10.1101/gad.1565107. PMID 17639082. 
  6. ↑ "An essential role for LEDGF/p75 in HIV integration". Science 314 (5798): 461–4. October 2006. doi:10.1126/science.1132319. PMID 16959972. Bibcode: 2006Sci...314..461L. 
  7. ↑ "Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication". Nat. Chem. Biol. 6 (6): 442–8. June 2010. doi:10.1038/nchembio.370. PMID 20473303. 
  8. ↑ 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. PMID 25056311. 
  9. ↑ 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. PMID 22615581. 
  10. ↑ 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. PMID 28384324. 
  11. ↑ "Virological and cellular roles of the transcriptional coactivator LEDGF/p75". HIV Interactions with Host Cell Proteins. Current Topics in Microbiology and Immunology. 339. 2009. 125–46. doi:10.1007/978-3-642-02175-6_7. ISBN 978-3-642-02174-9. 
  12. ↑ "Solution structure of the HIV-1 integrase-binding domain in LEDGF/p75". Nat. Struct. Mol. Biol. 12 (6): 526–32. June 2005. doi:10.1038/nsmb937. PMID 15895093. 
  13. ↑ "A novel transcriptional coactivator, p52, functionally interacts with the essential splicing factor ASF/SF2". Mol. Cell 2 (6): 751–9. December 1998. doi:10.1016/S1097-2765(00)80290-7. PMID 9885563. 
  14. ↑ "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. January 2010. doi:10.1074/jbc.M109.036491. PMID 19864417. 

Further reading




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