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6emo

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Current revision

Solution structure of the LEDGF/p75 IBD - JPO2 (aa 1-32) complex

Structural highlights

6emo 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.
Method:	Solution NMR
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

CDA7L_HUMAN Plays a role in transcriptional regulation as a repressor that inhibits monoamine oxidase A (MAOA) activity and gene expression by binding to the promoter. Plays an important oncogenic role in mediating the full transforming effect of MYC in medulloblastoma cells. Involved in apoptotic signaling pathways; May act downstream of P38-kinase and BCL-2, but upstream of CASP3/caspase-3 as well as CCND1/cyclin D1 and E2F1.^[1] ^[2] ^[3] 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.^[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

↑ Chen K, Ou XM, Chen G, Choi SH, Shih JC. R1, a novel repressor of the human monoamine oxidase A. J Biol Chem. 2005 Mar 25;280(12):11552-9. PMID:15654081 doi:10.1074/jbc.M410033200
↑ Huang A, Ho CS, Ponzielli R, Barsyte-Lovejoy D, Bouffet E, Picard D, Hawkins CE, Penn LZ. Identification of a novel c-Myc protein interactor, JPO2, with transforming activity in medulloblastoma cells. Cancer Res. 2005 Jul 1;65(13):5607-19. PMID:15994933 doi:10.1158/0008-5472.CAN-05-0500
↑ Ou XM, Chen K, Shih JC. Monoamine oxidase A and repressor R1 are involved in apoptotic signaling pathway. Proc Natl Acad Sci U S A. 2006 Jul 18;103(29):10923-8. PMID:16829576 doi:10.1073/pnas.0601515103
↑ 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
↑ 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/6emo"

Categories: Homo sapiens | Large Structures | Veverka V

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[6emo]] 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=6EMO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6EMO FirstGlance]. <br>
-</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=6emo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6emo OCA], [https://pdbe.org/6emo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6emo RCSB], [https://www.ebi.ac.uk/pdbsum/6emo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6emo ProSAT]</span></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</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=6emo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6emo OCA], [https://pdbe.org/6emo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6emo RCSB], [https://www.ebi.ac.uk/pdbsum/6emo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6emo ProSAT]</span></td></tr>
 </table>
 == Disease ==

6emo

From Proteopedia

Current revision

Solution structure of the LEDGF/p75 IBD - JPO2 (aa 1-32) complex

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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