6emr

From Proteopedia

(Difference between revisions)

Revision as of 10:43, 14 June 2023

Solution structure of the LEDGF/p75 IBD - IWS1 (aa 446-548) complex

Structural highlights

6emr is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

PSIP1_HUMAN Note=A chromosomal aberration involving PSIP1 is associated with pediatric acute myeloid leukemia (AML) with intermediate characteristics between M2-M3 French-American-British (FAB) subtypes. Translocation t(9;11)(p22;p15) with NUP98. The chimeric transcript is an in-frame fusion of NUP98 exon 8 to PSIP1/LEDGF exon 4.

Function

PSIP1_HUMAN Transcriptional coactivator involved in neuroepithelial stem cell differentiation and neurogenesis. Involved in particular in lens epithelial cell gene regulation and stress responses. May play an important role in lens epithelial to fiber cell terminal differentiation. May play a protective role during stress-induced apoptosis. Isoform 2 is a more general and stronger transcriptional coactivator. Isoform 2 may also act as an adapter to coordinate pre-mRNA splicing. Cellular cofactor for lentiviral integration.^[1] IWS1_HUMAN Transcription factor which plays a key role in defining the composition of the RNA polymerase II (RNAPII) elongation complex and in modulating the production of mature mRNA transcripts. Acts as an assembly factor to recruit various factors to the RNAPII elongation complex and is recruited to the complex via binding to the transcription elongation factor SUPT6H bound to the C-terminal domain (CTD) of the RNAPII subunit RPB1 (POLR2A). The SUPT6H:IWS1:CTD complex recruits mRNA export factors (ALYREF/THOC4, EXOSC10) as well as histone modifying enzymes (such as SETD2) to ensure proper mRNA splicing, efficient mRNA export and elongation-coupled H3K36 methylation, a signature chromatin mark of active transcription.^[2] ^[3] ^[4]

Publication Abstract from PubMed

Lens epithelium-derived growth factor/p75 (LEDGF/p75, or PSIP1) is a transcriptional coactivator that tethers other proteins to gene bodies. The chromatin tethering function of LEDGF/p75 is hijacked by HIV integrase to ensure viral integration at sites of active transcription. LEDGF/p75 is also important for the development of mixed-lineage leukemia (MLL), where it tethers the MLL1 fusion complex at aberrant MLL targets, inducing malignant transformation. However, little is known about how the LEDGF/p75 protein interaction network is regulated. Here, we obtained solution structures of the complete interfaces between the LEDGF/p75 integrase binding domain (IBD) and its cellular binding partners and validated another binding partner, Mediator subunit 1 (MED1). We reveal that structurally conserved IBD-binding motifs (IBMs) on known LEDGF/p75 binding partners can be regulated by phosphorylation, permitting switching between low- and high-affinity states. Finally, we show that elimination of IBM phosphorylation sites on MLL1 disrupts the oncogenic potential of primary MLL1-rearranged leukemic cells. Our results demonstrate that kinase-dependent phosphorylation of MLL1 represents a previously unknown oncogenic dependency that may be harnessed in the treatment of MLL-rearranged leukemia.

Affinity switching of the LEDGF/p75 IBD interactome is governed by kinase-dependent phosphorylation.,Sharma S, Cermakova K, De Rijck J, Demeulemeester J, Fabry M, El Ashkar S, Van Belle S, Lepsik M, Tesina P, Duchoslav V, Novak P, Hubalek M, Srb P, Christ F, Rezacova P, Hodges HC, Debyser Z, Veverka V Proc Natl Acad Sci U S A. 2018 Jul 11. pii: 1803909115. doi:, 10.1073/pnas.1803909115. PMID:29997176^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Chylack LT Jr, Fu L, Mancini R, Martin-Rehrmann MD, Saunders AJ, Konopka G, Tian D, Hedley-Whyte ET, Folkerth RD, Goldstein LE. Lens epithelium-derived growth factor (LEDGF/p75) expression in fetal and adult human brain. Exp Eye Res. 2004 Dec;79(6):941-8. PMID:15642333 doi:S0014-4835(04)00250-7
↑ Liu Z, Zhou Z, Chen G, Bao S. A putative transcriptional elongation factor hIws1 is essential for mammalian cell proliferation. Biochem Biophys Res Commun. 2007 Feb 2;353(1):47-53. doi:, 10.1016/j.bbrc.2006.11.133. Epub 2006 Dec 5. PMID:17184735 doi:http://dx.doi.org/10.1016/j.bbrc.2006.11.133
↑ Yoh SM, Cho H, Pickle L, Evans RM, Jones KA. The Spt6 SH2 domain binds Ser2-P RNAPII to direct Iws1-dependent mRNA splicing and export. Genes Dev. 2007 Jan 15;21(2):160-74. doi: 10.1101/gad.1503107. PMID:17234882 doi:http://dx.doi.org/10.1101/gad.1503107
↑ Yoh SM, Lucas JS, Jones KA. The Iws1:Spt6:CTD complex controls cotranscriptional mRNA biosynthesis and HYPB/Setd2-mediated histone H3K36 methylation. Genes Dev. 2008 Dec 15;22(24):3422-34. doi: 10.1101/gad.1720008. PMID:19141475 doi:http://dx.doi.org/10.1101/gad.1720008
↑ Sharma S, Cermakova K, De Rijck J, Demeulemeester J, Fabry M, El Ashkar S, Van Belle S, Lepsik M, Tesina P, Duchoslav V, Novak P, Hubalek M, Srb P, Christ F, Rezacova P, Hodges HC, Debyser Z, Veverka V. Affinity switching of the LEDGF/p75 IBD interactome is governed by kinase-dependent phosphorylation. Proc Natl Acad Sci U S A. 2018 Jul 11. pii: 1803909115. doi:, 10.1073/pnas.1803909115. PMID:29997176 doi:http://dx.doi.org/10.1073/pnas.1803909115

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6emr"

Categories: Homo sapiens | Large Structures | Veverka V

@@ Line 1: / Line 1: @@
 ==Solution structure of the LEDGF/p75 IBD - IWS1 (aa 446-548) complex==
-<StructureSection load='6emr' size='340' side='right'caption='[[6emr]], [[NMR_Ensembles_of_Models | 40 NMR models]]' scene=''>
+<StructureSection load='6emr' size='340' side='right'caption='[[6emr]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6emr]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EMR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EMR FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6emr]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EMR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6EMR FirstGlance]. <br>
-</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">IWS1, IWS1L ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6emr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6emr OCA], [https://pdbe.org/6emr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6emr RCSB], [https://www.ebi.ac.uk/pdbsum/6emr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6emr ProSAT]</span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6emr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6emr OCA], [http://pdbe.org/6emr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6emr RCSB], [http://www.ebi.ac.uk/pdbsum/6emr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6emr ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://www.uniprot.org/uniprot/PSIP1_HUMAN PSIP1_HUMAN]] Note=A chromosomal aberration involving PSIP1 is associated with pediatric acute myeloid leukemia (AML) with intermediate characteristics between M2-M3 French-American-British (FAB) subtypes. Translocation t(9;11)(p22;p15) with NUP98. The chimeric transcript is an in-frame fusion of NUP98 exon 8 to PSIP1/LEDGF exon 4.
+[https://www.uniprot.org/uniprot/PSIP1_HUMAN PSIP1_HUMAN] Note=A chromosomal aberration involving PSIP1 is associated with pediatric acute myeloid leukemia (AML) with intermediate characteristics between M2-M3 French-American-British (FAB) subtypes. Translocation t(9;11)(p22;p15) with NUP98. The chimeric transcript is an in-frame fusion of NUP98 exon 8 to PSIP1/LEDGF exon 4.
 == Function ==
-[[http://www.uniprot.org/uniprot/PSIP1_HUMAN PSIP1_HUMAN]] Transcriptional coactivator involved in neuroepithelial stem cell differentiation and neurogenesis. Involved in particular in lens epithelial cell gene regulation and stress responses. May play an important role in lens epithelial to fiber cell terminal differentiation. May play a protective role during stress-induced apoptosis. Isoform 2 is a more general and stronger transcriptional coactivator. Isoform 2 may also act as an adapter to coordinate pre-mRNA splicing. Cellular cofactor for lentiviral integration.<ref>PMID:15642333</ref>
+[https://www.uniprot.org/uniprot/PSIP1_HUMAN PSIP1_HUMAN] Transcriptional coactivator involved in neuroepithelial stem cell differentiation and neurogenesis. Involved in particular in lens epithelial cell gene regulation and stress responses. May play an important role in lens epithelial to fiber cell terminal differentiation. May play a protective role during stress-induced apoptosis. Isoform 2 is a more general and stronger transcriptional coactivator. Isoform 2 may also act as an adapter to coordinate pre-mRNA splicing. Cellular cofactor for lentiviral integration.<ref>PMID:15642333</ref> [https://www.uniprot.org/uniprot/IWS1_HUMAN IWS1_HUMAN] Transcription factor which plays a key role in defining the composition of the RNA polymerase II (RNAPII) elongation complex and in modulating the production of mature mRNA transcripts. Acts as an assembly factor to recruit various factors to the RNAPII elongation complex and is recruited to the complex via binding to the transcription elongation factor SUPT6H bound to the C-terminal domain (CTD) of the RNAPII subunit RPB1 (POLR2A). The SUPT6H:IWS1:CTD complex recruits mRNA export factors (ALYREF/THOC4, EXOSC10) as well as histone modifying enzymes (such as SETD2) to ensure proper mRNA splicing, efficient mRNA export and elongation-coupled H3K36 methylation, a signature chromatin mark of active transcription.<ref>PMID:17184735</ref> <ref>PMID:17234882</ref> <ref>PMID:19141475</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 24: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Veverka, V]]
+[[Category: Veverka V]]
-[[Category: Epigenetic]]
-[[Category: Leukemia]]
-[[Category: Protein-protein complex]]
-[[Category: Transcription]]

6emr

From Proteopedia

Revision as of 10:43, 14 June 2023

Solution structure of the LEDGF/p75 IBD - IWS1 (aa 446-548) complex

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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