PSIP1: Difference between revisions

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{{Infobox_gene}}
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'''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]].<ref name="entrez">{{cite web | title = Entrez Gene: PSIP1 PC4 and SFRS1 interacting protein 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=11168| accessdate = }}</ref><ref name="pmid10721720">{{cite journal | vauthors = Singh DP, Kimura A, Chylack LT, Shinohara T | title = Lens epithelium-derived growth factor (LEDGF/p75) and p52 are derived from a single gene by alternative splicing | journal = Gene | volume = 242 | issue = 1-2 | pages = 265–73  | date = January 2000 | pmid = 10721720 | doi = 10.1016/S0378-1119(99)00506-5 }}</ref>
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
}}


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{GNF_Protein_box
| image = PBB_Protein_PSIP1_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1z9e.
| PDB = {{PDB2|1z9e}}, {{PDB2|2b4j}}
| Name = PC4 and SFRS1 interacting protein 1
| HGNCid = 9527
| Symbol = PSIP1
| AltSymbols =; p75; p52; DFS70; LEDGF; MGC74712; PAIP; PSIP2
| OMIM = 603620
| ECnumber = 
| Homologene = 13242
| MGIid = 2142116
| GeneAtlas_image1 = PBB_GE_PSIP1_210758_at_tn.png
| GeneAtlas_image2 = PBB_GE_PSIP1_205961_s_at_tn.png
| GeneAtlas_image3 = PBB_GE_PSIP1_209337_at_tn.png
| Function = {{GNF_GO|id=GO:0003677 |text = DNA binding}}
| Component = {{GNF_GO|id=GO:0005634 |text = nucleus}}
| Process = {{GNF_GO|id=GO:0006350 |text = transcription}} {{GNF_GO|id=GO:0006355 |text = regulation of transcription, DNA-dependent}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 11168
    | Hs_Ensembl = ENSG00000164985
    | Hs_RefseqProtein = NP_066967
    | Hs_RefseqmRNA = NM_021144
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 9
    | Hs_GenLoc_start = 15454064
    | Hs_GenLoc_end = 15501017
    | Hs_Uniprot = O75475
    | Mm_EntrezGene = 101739
    | Mm_Ensembl = ENSMUSG00000028484
    | Mm_RefseqmRNA = NM_133948
    | Mm_RefseqProtein = NP_598709
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 4
    | Mm_GenLoc_start = 82926911
    | Mm_GenLoc_end = 82957621
    | Mm_Uniprot = Q05CD2
  }}
}}
'''PC4 and SFRS1 interacting protein 1''', also known as '''PSIP1''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: PSIP1 PC4 and SFRS1 interacting protein 1| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=11168| accessdate = }}</ref> It is thought to impede the replication of HIV.


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
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 (genetics)|coactivator]], gained prominence as a host factor that assists HIV integration<ref name="pmid12407101">{{cite journal | vauthors = Cherepanov P, Maertens G, Proost P, Devreese B, Van Beeumen J, Engelborghs Y, De Clercq E, Debyser Z | title = HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells | journal = J. Biol. Chem. | volume = 278 | issue = 1 | pages = 372–81  | date = January 2003 | pmid = 12407101 | doi = 10.1074/jbc.M209278200 }}</ref> and is probably the only integrase interactor whose knock-down severely affects the HIV integration levels.<ref name="pmid16439544">{{cite journal | vauthors = Vandekerckhove L, Christ F, Van Maele B, De Rijck J, Gijsbers R, Van den Haute C, Witvrouw M, Debyser Z | title = Transient and stable knockdown of the integrase cofactor LEDGF/p75 reveals its role in the replication cycle of human immunodeficiency virus | journal = J. Virol. | volume = 80 | issue = 4 | pages = 1886–96  | date = February 2006 | pmid = 16439544 | pmc = 1367129 | doi = 10.1128/JVI.80.4.1886-1896.2006 }}</ref><ref name="pmid17639082">{{cite journal | vauthors = Shun MC, Raghavendra NK, Vandegraaff N, Daigle JE, Hughes S, Kellam P, Cherepanov P, Engelman A | title = LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration | journal = Genes Dev. | volume = 21 | issue = 14 | pages = 1767–78  | date = July 2007 | pmid = 17639082 | pmc = 1920171 | doi = 10.1101/gad.1565107 }}</ref><ref name="pmid16959972">{{cite journal | vauthors = Llano M, Saenz DT, Meehan A, Wongthida P, Peretz M, Walker WH, Teo W, Poeschla EM | title = An essential role for LEDGF/p75 in HIV integration | journal = Science | volume = 314 | issue = 5798 | pages = 461–4  | date = October 2006 | pmid = 16959972 | doi = 10.1126/science.1132319 }}</ref> The interaction between HIV [[integrase]] and human LEDGF/p75 is a promising target for anti-HIV drug discovery.<ref name="pmid20473303">{{cite journal | vauthors = 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 | title = Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication | journal = Nat. Chem. Biol. | volume = 6 | issue = 6 | pages = 442–8 | date = June 2010 | pmid = 20473303 | doi = 10.1038/nchembio.370 }}</ref> LEDGF/p75 recruits MLL complexes to HOX genes to regulate their expression.<ref>{{Cite journal|last=Pradeepa|first=Madapura M.|last2=Grimes|first2=Graeme R.|last3=Taylor|first3=Gillian C. A.|last4=Sutherland|first4=Heidi G.|last5=Bickmore|first5=Wendy A.|date=2014-08-18|title=Psip1/Ledgf p75 restrains Hox gene expression by recruiting both trithorax and polycomb group proteins|url=https://academic.oup.com/nar/article/42/14/9021/1291770/Psip1-Ledgf-p75-restrains-Hox-gene-expression-by|journal=Nucleic Acids Research|volume=42|issue=14|pages=9021–9032|doi=10.1093/nar/gku647|issn=0305-1048|pmc=4132756|pmid=25056311}}</ref> LEDGF/p52 is shown to recruit splicing factors to H3K36 trimethylated chromatin to modulate alternative splicing,<ref>{{Cite journal|last=Pradeepa|first=Madapura M.|last2=Sutherland|first2=Heidi G.|last3=Ule|first3=Jernej|last4=Grimes|first4=Graeme R.|last5=Bickmore|first5=Wendy A.|date=2012-05-17|title=Psip1/Ledgf p52 Binds Methylated Histone H3K36 and Splicing Factors and Contributes to the Regulation of Alternative Splicing|url=http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1002717|journal=PLOS Genetics|volume=8|issue=5|pages=e1002717|doi=10.1371/journal.pgen.1002717|issn=1553-7404|pmc=3355077|pmid=22615581}}</ref> also regulates HOTTIP '''lncRNA''', which is shown to regulate HOX genes ''in cis''.<ref>{{Cite journal|last=Pradeepa|first=Madapura M.|last2=McKenna|first2=Fionnuala|last3=Taylor|first3=Gillian C. A.|last4=Bengani|first4=Hemant|last5=Grimes|first5=Graeme R.|last6=Wood|first6=Andrew J.|last7=Bhatia|first7=Shipra|last8=Bickmore|first8=Wendy A.|date=2017-04-06|title=Psip1/p52 regulates posterior Hoxa genes through activation of lncRNA Hottip|url=http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1006677|journal=PLOS Genetics|volume=13|issue=4|pages=e1006677|doi=10.1371/journal.pgen.1006677|issn=1553-7404|pmc=5383017|pmid=28384324}}</ref>
{{PBB_Summary
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| summary_text =  
}}


==References==
== Structure ==
{{reflist|2}}
 
{{refbegin | 2}}
LEDGF/p75 is a 60kDa, 530-amino-acid-long protein.<ref name="pmid20012527">{{cite journal | vauthors = Llano M, Morrison J, Poeschla EM | title = Virological and cellular roles of the transcriptional coactivator LEDGF/p75 | journal = Curr. Top. Microbiol. Immunol. | volume = 339 | issue = | pages = 125–46 | year = 2009 | pmid = 20012527 | pmc = 3093762 | doi = 10.1007/978-3-642-02175-6_7 }}</ref> The N-terminal portion of the protein consists of a PWWP domain, a [[Nuclear localisation sequence|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,<ref name="pmid15895093">{{cite journal | vauthors = Cherepanov P, Sun ZY, Rahman S, Maertens G, Wagner G, Engelman A | title = Solution structure of the HIV-1 integrase-binding domain in LEDGF/p75 | journal = Nat. Struct. Mol. Biol. | volume = 12 | issue = 6 | pages = 526–32 | date = June 2005 | pmid = 15895093 | doi = 10.1038/nsmb937}}</ref> which interacts with [[Lentivirus|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.
{{PBB_Further_reading
 
| citations =
== Interactions ==
*{{cite journal  | author=Van Maele B, Debyser Z |title=HIV-1 integration: an interplay between HIV-1 integrase, cellular and viral proteins. |journal=AIDS reviews |volume=7 |issue= 1 |pages= 26-43 |year= 2005 |pmid= 15875659 |doi= }}
 
*{{cite journal | author=Van Maele B, Busschots K, Vandekerckhove L, ''et al.'' |title=Cellular co-factors of HIV-1 integration. |journal=Trends Biochem. Sci. |volume=31 |issue= 2 |pages= 98-105 |year= 2006 |pmid= 16403635 |doi= 10.1016/j.tibs.2005.12.002 }}
PSIP1 has been shown to [[Protein-protein interaction|interact]] with the proteins [[ASF/SF2]], JPO2, Cdc7-Dbf4, and [[POGZ]] as well as the [[MEN1|menin]]/[[MLL (gene)|MLL]] protein complex.<ref name="pmid9885563">{{cite journal | vauthors = Ge H, Si Y, Wolffe AP | title = A novel transcriptional coactivator, p52, functionally interacts with the essential splicing factor ASF/SF2 | journal = Mol. Cell | volume = 2 | issue = 6 | pages = 751–9  | date = December 1998 | pmid = 9885563 | doi = 10.1016/S1097-2765(00)80290-7 }}</ref><ref name="pmid19864417">{{cite journal | vauthors = Hughes S, Jenkins V, Dar MJ, Engelman A, Cherepanov P | title = Transcriptional co-activator LEDGF interacts with Cdc7-activator of S-phase kinase (ASK) and stimulates its enzymatic activity | journal = J. Biol. Chem. | volume = 285 | issue = 1 | pages = 541–54  | date = January 2010 | pmid = 19864417 | pmc = 2804203 | doi = 10.1074/jbc.M109.036491 }}</ref>
*{{cite journal | author=Freed EO, Mouland AJ |title=The cell biology of HIV-1 and other retroviruses. |journal=Retrovirology |volume=3 |issue= |pages= 77 |year= 2006 |pmid= 17083721 |doi= 10.1186/1742-4690-3-77 }}
 
*{{cite journal | author=Ge H, Si Y, Roeder RG |title=Isolation of cDNAs encoding novel transcription coactivators p52 and p75 reveals an alternate regulatory mechanism of transcriptional activation. |journal=EMBO J. |volume=17 |issue= 22 |pages= 6723-9 |year= 1999 |pmid= 9822615 |doi= 10.1093/emboj/17.22.6723 }}
== References ==
*{{cite journal | author=Ge H, Si Y, Wolffe AP |title=A novel transcriptional coactivator, p52, functionally interacts with the essential splicing factor ASF/SF2. |journal=Mol. Cell |volume=2 |issue= 6 |pages= 751-9 |year= 1999 |pmid= 9885563 |doi= }}
{{reflist|35em}}
*{{cite journal | author=Singh DP, Ohguro N, Kikuchi T, ''et al.'' |title=Lens epithelium-derived growth factor: effects on growth and survival of lens epithelial cells, keratinocytes, and fibroblasts. |journal=Biochem. Biophys. Res. Commun. |volume=267 |issue= 1 |pages= 373-81 |year= 2000 |pmid= 10623627 |doi= 10.1006/bbrc.1999.1979 }}
 
*{{cite journal | author=Singh DP, Kimura A, Chylack LT, Shinohara T |title=Lens epithelium-derived growth factor (LEDGF/p75) and p52 are derived from a single gene by alternative splicing. |journal=Gene |volume=242 |issue= 1-2 |pages= 265-73 |year= 2000 |pmid= 10721720 |doi= }}
== Further reading==
*{{cite journal | author=Ochs RL, Muro Y, Si Y, ''et al.'' |title=Autoantibodies to DFS 70 kd/transcription coactivator p75 in atopic dermatitis and other conditions. |journal=J. Allergy Clin. Immunol. |volume=105 |issue= 6 Pt 1 |pages= 1211-20 |year= 2000 |pmid= 10856157 |doi=  }}
{{refbegin|35em}}
*{{cite journal | author=Kubo E, Fatma N, Sharma P, ''et al.'' |title=Transactivation of involucrin, a marker of differentiation in keratinocytes, by lens epithelium-derived growth factor (LEDGF). |journal=J. Mol. Biol. |volume=320 |issue= 5 |pages= 1053-63 |year= 2002 |pmid= 12126624 |doi= }}
* {{cite journal | vauthors = Shun MC, Raghavendra NK, Vandegraaff N, Daigle JE, Hughes S, Kellam P, Cherepanov P, Engelman A | title = LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration | journal = Genes Dev. | volume = 21 | issue = 14 | pages = 1767–78  | date = July 2007 | pmid = 17639082 | pmc = 1920171 | doi = 10.1101/gad.1565107 }}
*{{cite journal | author=Wu X, Daniels T, Molinaro C, ''et al.'' |title=Caspase cleavage of the nuclear autoantigen LEDGF/p75 abrogates its pro-survival function: implications for autoimmunity in atopic disorders. |journal=Cell Death Differ. |volume=9 |issue= 9 |pages= 915-25 |year= 2003 |pmid= 12181742 |doi= 10.1038/sj.cdd.4401063 }}
* {{cite journal | vauthors = Van Maele B, Debyser Z | title = HIV-1 integration: an interplay between HIV-1 integrase, cellular and viral proteins | journal = AIDS Rev | volume = 7 | issue = 1 | pages = 26–43 | year = 2005 | pmid = 15875659 | doi =  }}
*{{cite journal | author=Cherepanov P, Maertens G, Proost P, ''et al.'' |title=HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells. |journal=J. Biol. Chem. |volume=278 |issue= 1 |pages= 372-81 |year= 2003 |pmid= 12407101 |doi= 10.1074/jbc.M209278200 }}
* {{cite journal | vauthors = Van Maele B, Busschots K, Vandekerckhove L, Christ F, Debyser Z | title = Cellular co-factors of HIV-1 integration | journal = Trends Biochem. Sci. | volume = 31 | issue = 2 | pages = 98–105 | year = 2006 | pmid = 16403635 | doi = 10.1016/j.tibs.2005.12.002 }}
*{{cite journal | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
* {{cite journal | vauthors = Freed EO, Mouland AJ | title = The cell biology of HIV-1 and other retroviruses | journal = Retrovirology | volume = 3 | issue = | pages = 77 | year = 2006 | pmid = 17083721 | pmc = 1635732 | doi = 10.1186/1742-4690-3-77 }}
*{{cite journal | author=Maertens G, Cherepanov P, Pluymers W, ''et al.'' |title=LEDGF/p75 is essential for nuclear and chromosomal targeting of HIV-1 integrase in human cells. |journal=J. Biol. Chem. |volume=278 |issue= 35 |pages= 33528-39 |year= 2003 |pmid= 12796494 |doi= 10.1074/jbc.M303594200 }}
* {{cite journal | vauthors = Ge H, Si Y, Roeder RG | title = Isolation of cDNAs encoding novel transcription coactivators p52 and p75 reveals an alternate regulatory mechanism of transcriptional activation | journal = EMBO J. | volume = 17 | issue = 22 | pages = 6723–9 | year = 1998 | pmid = 9822615 | pmc = 1171017 | doi = 10.1093/emboj/17.22.6723 }}
*{{cite journal | author=Maertens G, Cherepanov P, Debyser Z, ''et al.'' |title=Identification and characterization of a functional nuclear localization signal in the HIV-1 integrase interactor LEDGF/p75. |journal=J. Biol. Chem. |volume=279 |issue= 32 |pages= 33421-9 |year= 2004 |pmid= 15163664 |doi= 10.1074/jbc.M404700200 }}
* {{cite journal | vauthors = Ge H, Si Y, Wolffe AP | title = A novel transcriptional coactivator, p52, functionally interacts with the essential splicing factor ASF/SF2 | journal = Mol. Cell | volume = 2 | issue = 6 | pages = 751–9 | year = 1998 | pmid = 9885563 | doi = 10.1016/S1097-2765(00)80290-7 }}
*{{cite journal | author=Beausoleil SA, Jedrychowski M, Schwartz D, ''et al.'' |title=Large-scale characterization of HeLa cell nuclear phosphoproteins. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=101 |issue= 33 |pages= 12130-5 |year= 2004 |pmid= 15302935 |doi= 10.1073/pnas.0404720101 }}
* {{cite journal | vauthors = Singh DP, Ohguro N, Kikuchi T, Sueno T, Reddy VN, Yuge K, Chylack LT, Shinohara T | title = Lens epithelium-derived growth factor: effects on growth and survival of lens epithelial cells, keratinocytes, and fibroblasts | journal = Biochem. Biophys. Res. Commun. | volume = 267 | issue = 1 | pages = 373–81 | year = 2000 | pmid = 10623627 | doi = 10.1006/bbrc.1999.1979 }}
*{{cite journal | author=Llano M, Vanegas M, Fregoso O, ''et al.'' |title=LEDGF/p75 determines cellular trafficking of diverse lentiviral but not murine oncoretroviral integrase proteins and is a component of functional lentiviral preintegration complexes. |journal=J. Virol. |volume=78 |issue= 17 |pages= 9524-37 |year= 2004 |pmid= 15308744 |doi= 10.1128/JVI.78.17.9524-9537.2004 }}
* {{cite journal | vauthors = Singh DP, Kimura A, Chylack LT, Shinohara T | title = Lens epithelium-derived growth factor (LEDGF/p75) and p52 are derived from a single gene by alternative splicing | journal = Gene | volume = 242 | issue = 1-2 | pages = 265–73 | year = 2000 | pmid = 10721720 | doi = 10.1016/S0378-1119(99)00506-5 }}
*{{cite journal | author=Cherepanov P, Devroe E, Silver PA, Engelman A |title=Identification of an evolutionarily conserved domain in human lens epithelium-derived growth factor/transcriptional co-activator p75 (LEDGF/p75) that binds HIV-1 integrase. |journal=J. Biol. Chem. |volume=279 |issue= 47 |pages= 48883-92 |year= 2005 |pmid= 15371438 |doi= 10.1074/jbc.M406307200 }}
* {{cite journal | vauthors = Ochs RL, Muro Y, Si Y, Ge H, Chan EK, Tan EM | title = Autoantibodies to DFS 70 kd/transcription coactivator p75 in atopic dermatitis and other conditions | journal = J. Allergy Clin. Immunol. | volume = 105 | issue = 6 Pt 1 | pages = 1211–20 | year = 2000 | pmid = 10856157 | doi = 10.1067/mai.2000.107039 }}
*{{cite journal | author=Llano M, Delgado S, Vanegas M, Poeschla EM |title=Lens epithelium-derived growth factor/p75 prevents proteasomal degradation of HIV-1 integrase. |journal=J. Biol. Chem. |volume=279 |issue= 53 |pages= 55570-7 |year= 2005 |pmid= 15475359 |doi= 10.1074/jbc.M408508200 }}
* {{cite journal | vauthors = Kubo E, Fatma N, Sharma P, Shinohara T, Chylack LT, Akagi Y, Singh DP | title = Transactivation of involucrin, a marker of differentiation in keratinocytes, by lens epithelium-derived growth factor (LEDGF) | journal = J. Mol. Biol. | volume = 320 | issue = 5 | pages = 1053–63 | year = 2002 | pmid = 12126624 | doi = 10.1016/S0022-2836(02)00551-X }}
*{{cite journal | author=Ogawa Y, Sugiura K, Watanabe A, ''et al.'' |title=Autoantigenicity of DFS70 is restricted to the conformational epitope of C-terminal alpha-helical domain. |journal=J. Autoimmun. |volume=23 |issue= 3 |pages= 221-31 |year= 2005 |pmid= 15501393 |doi= 10.1016/j.jaut.2004.07.003 }}
* {{cite journal | vauthors = Wu X, Daniels T, Molinaro C, Lilly MB, Casiano CA | title = Caspase cleavage of the nuclear autoantigen LEDGF/p75 abrogates its pro-survival function: implications for autoimmunity in atopic disorders | journal = Cell Death Differ. | volume = 9 | issue = 9 | pages = 915–25 | year = 2002 | pmid = 12181742 | doi = 10.1038/sj.cdd.4401063 }}
*{{cite journal | author=Okamoto M, Ogawa Y, Watanabe A, ''et al.'' |title=Autoantibodies to DFS70/LEDGF are increased in alopecia areata patients. |journal=J. Autoimmun. |volume=23 |issue= 3 |pages= 257-66 |year= 2005 |pmid= 15501396 |doi= 10.1016/j.jaut.2004.07.004 }}
* {{cite journal | vauthors = Cherepanov P, Maertens G, Proost P, Devreese B, Van Beeumen J, Engelborghs Y, De Clercq E, Debyser Z | title = HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells | journal = J. Biol. Chem. | volume = 278 | issue = 1 | pages = 372–81 | year = 2003 | pmid = 12407101 | doi = 10.1074/jbc.M209278200 }}
}}
* {{cite journal | vauthors = Maertens G, Cherepanov P, Pluymers W, Busschots K, De Clercq E, Debyser Z, Engelborghs Y | title = LEDGF/p75 is essential for nuclear and chromosomal targeting of HIV-1 integrase in human cells | journal = J. Biol. Chem. | volume = 278 | issue = 35 | pages = 33528–39 | year = 2003 | pmid = 12796494 | doi = 10.1074/jbc.M303594200 }}
* {{cite journal | vauthors = Maertens G, Cherepanov P, Debyser Z, Engelborghs Y, Engelman A | title = Identification and characterization of a functional nuclear localization signal in the HIV-1 integrase interactor LEDGF/p75 | journal = J. Biol. Chem. | volume = 279 | issue = 32 | pages = 33421–9 | year = 2004 | pmid = 15163664 | doi = 10.1074/jbc.M404700200 }}
* {{cite journal | vauthors = Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP | title = Large-scale characterization of HeLa cell nuclear phosphoproteins | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 101 | issue = 33 | pages = 12130–5 | year = 2004 | pmid = 15302935 | pmc = 514446 | doi = 10.1073/pnas.0404720101 }}
* {{cite journal | vauthors = Llano M, Vanegas M, Fregoso O, Saenz D, Chung S, Peretz M, Poeschla EM | title = LEDGF/p75 determines cellular trafficking of diverse lentiviral but not murine oncoretroviral integrase proteins and is a component of functional lentiviral preintegration complexes | journal = J. Virol. | volume = 78 | issue = 17 | pages = 9524–37 | year = 2004 | pmid = 15308744 | pmc = 506940 | doi = 10.1128/JVI.78.17.9524-9537.2004 }}
* {{cite journal | vauthors = Cherepanov P, Devroe E, Silver PA, Engelman A | title = Identification of an evolutionarily conserved domain in human lens epithelium-derived growth factor/transcriptional co-activator p75 (LEDGF/p75) that binds HIV-1 integrase | journal = J. Biol. Chem. | volume = 279 | issue = 47 | pages = 48883–92 | year = 2004 | pmid = 15371438 | doi = 10.1074/jbc.M406307200 }}
* {{cite journal | vauthors = Llano M, Delgado S, Vanegas M, Poeschla EM | title = Lens epithelium-derived growth factor/p75 prevents proteasomal degradation of HIV-1 integrase | journal = J. Biol. Chem. | volume = 279 | issue = 53 | pages = 55570–7 | year = 2004 | pmid = 15475359 | doi = 10.1074/jbc.M408508200 }}
* {{cite journal | vauthors = Ogawa Y, Sugiura K, Watanabe A, Kunimatsu M, Mishima M, Tomita Y, Muro Y | title = Autoantigenicity of DFS70 is restricted to the conformational epitope of C-terminal alpha-helical domain | journal = J. Autoimmun. | volume = 23 | issue = 3 | pages = 221–31 | year = 2004 | pmid = 15501393 | doi = 10.1016/j.jaut.2004.07.003 }}
* {{cite journal | vauthors = Okamoto M, Ogawa Y, Watanabe A, Sugiura K, Shimomura Y, Aoki N, Nagasaka T, Tomita Y, Muro Y | title = Autoantibodies to DFS70/LEDGF are increased in alopecia areata patients | journal = J. Autoimmun. | volume = 23 | issue = 3 | pages = 257–66 | year = 2004 | pmid = 15501396 | doi = 10.1016/j.jaut.2004.07.004 }}
{{refend}}
{{refend}}


{{protein-stub}}
{{PDB Gallery|geneid=11168}}
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Revision as of 18:49, 7 September 2017

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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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".
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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. PMID 16959972.
  7. ↑ 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.
  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. PMC 4132756. 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. PMC 3355077. 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. PMC 5383017. PMID 28384324.
  11. ↑ Llano M, Morrison J, Poeschla EM (2009). "Virological and cellular roles of the transcriptional coactivator LEDGF/p75". Curr. Top. Microbiol. Immunol. 339: 125–46. doi:10.1007/978-3-642-02175-6_7. PMC 3093762. PMID 20012527.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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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