6kn5

From Proteopedia

(Difference between revisions)

Revision as of 11:44, 23 March 2022

Crystal structure of AFF4 C-terminal domain

Structural highlights

6kn5 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Gene:	AFF4, AF5Q31, MCEF, HSPC092 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[AFF4_HUMAN] Note=A chromosomal aberration involving AFF4 is found in acute lymphoblastic leukemia (ALL). Insertion ins(5;11)(q31;q13q23) that forms a MLL-AFF4 fusion protein.

Function

[AFF4_HUMAN] Key component of the super elongation complex (SEC), a complex required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA. In the SEC complex, AFF4 acts as a central scaffold that recruits other factors through direct interactions with ELL proteins (ELL, ELL2 or ELL3) and the P-TEFb complex. In case of infection by HIV-1 virus, the SEC complex is recruited by the viral Tat protein to stimulate viral gene expression.^[1] ^[2] ^[3]

Publication Abstract from PubMed

As approximately 70% of human breast tumors are estrogen receptor alpha (ERalpha)-positive, estrogen and ERalpha play essential roles in breast cancer development. By interrupting the ERalpha signaling pathway, endocrine therapy has been proven to be an effective therapeutic strategy. In this study, we identified a mechanism by which Transcription Start Site (TSS)-associated histone H3K27 acetylation signals the Super Elongation Complex (SEC) to regulate transcriptional elongation of the ESR1 (ERalpha) gene. SEC interacts with H3K27ac on ESR1 TSS through its scaffold protein AFF4. Depletion of AFF4 by siRNA or CRISPR/Cas9 dramatically reduces expression of ESR1 and its target genes, consequently inhibiting breast cancer cell growth. More importantly, a AFF4 mutant which lacks H3K27ac interaction failed to rescue ESR1 gene expression, suggesting H3K27 acetylation at TSS region is a key mark bridging the transition from transcriptional initiation to elongation, and perturbing SEC function can be an alternative strategy for targeting ERalpha signaling pathway at chromatin level.

Acetylation of histone H3K27 signals the transcriptional elongation for estrogen receptor alpha.,Gao Y, Chen L, Han Y, Wu F, Yang WS, Zhang Z, Huo T, Zhu Y, Yu C, Kim H, Lee M, Tang Z, Phillips K, He B, Jung SY, Song Y, Zhu B, Xu RM, Feng Q Commun Biol. 2020 Apr 7;3(1):165. doi: 10.1038/s42003-020-0898-0. PMID:32265480^[4]

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

References

↑ He N, Liu M, Hsu J, Xue Y, Chou S, Burlingame A, Krogan NJ, Alber T, Zhou Q. HIV-1 Tat and host AFF4 recruit two transcription elongation factors into a bifunctional complex for coordinated activation of HIV-1 transcription. Mol Cell. 2010 May 14;38(3):428-38. doi: 10.1016/j.molcel.2010.04.013. PMID:20471948 doi:10.1016/j.molcel.2010.04.013
↑ Lin C, Smith ER, Takahashi H, Lai KC, Martin-Brown S, Florens L, Washburn MP, Conaway JW, Conaway RC, Shilatifard A. AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia. Mol Cell. 2010 Feb 12;37(3):429-37. doi: 10.1016/j.molcel.2010.01.026. PMID:20159561 doi:10.1016/j.molcel.2010.01.026
↑ Chou S, Upton H, Bao K, Schulze-Gahmen U, Samelson AJ, He N, Nowak A, Lu H, Krogan NJ, Zhou Q, Alber T. HIV-1 Tat recruits transcription elongation factors dispersed along a flexible AFF4 scaffold. Proc Natl Acad Sci U S A. 2013 Jan 8;110(2):E123-31. doi:, 10.1073/pnas.1216971110. Epub 2012 Dec 18. PMID:23251033 doi:10.1073/pnas.1216971110
↑ Gao Y, Chen L, Han Y, Wu F, Yang WS, Zhang Z, Huo T, Zhu Y, Yu C, Kim H, Lee M, Tang Z, Phillips K, He B, Jung SY, Song Y, Zhu B, Xu RM, Feng Q. Acetylation of histone H3K27 signals the transcriptional elongation for estrogen receptor alpha. Commun Biol. 2020 Apr 7;3(1):165. doi: 10.1038/s42003-020-0898-0. PMID:32265480 doi:http://dx.doi.org/10.1038/s42003-020-0898-0

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/6kn5"

@@ Line 1: / Line 1: @@
 ==Crystal structure of AFF4 C-terminal domain==
-<StructureSection load='6kn5' size='340' side='right'caption='[[6kn5]]' scene=''>
+<StructureSection load='6kn5' size='340' side='right'caption='[[6kn5]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6KN5 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6KN5 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6kn5]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6KN5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6KN5 FirstGlance]. <br>
-</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6kn5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6kn5 OCA], [http://pdbe.org/6kn5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6kn5 RCSB], [http://www.ebi.ac.uk/pdbsum/6kn5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6kn5 ProSAT]</span></td></tr>
+</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AFF4, AF5Q31, MCEF, HSPC092 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6kn5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6kn5 OCA], [https://pdbe.org/6kn5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6kn5 RCSB], [https://www.ebi.ac.uk/pdbsum/6kn5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6kn5 ProSAT]</span></td></tr>
 </table>
+== Disease ==
+[[https://www.uniprot.org/uniprot/AFF4_HUMAN AFF4_HUMAN]] Note=A chromosomal aberration involving AFF4 is found in acute lymphoblastic leukemia (ALL). Insertion ins(5;11)(q31;q13q23) that forms a MLL-AFF4 fusion protein.
+== Function ==
+[[https://www.uniprot.org/uniprot/AFF4_HUMAN AFF4_HUMAN]] Key component of the super elongation complex (SEC), a complex required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA. In the SEC complex, AFF4 acts as a central scaffold that recruits other factors through direct interactions with ELL proteins (ELL, ELL2 or ELL3) and the P-TEFb complex. In case of infection by HIV-1 virus, the SEC complex is recruited by the viral Tat protein to stimulate viral gene expression.<ref>PMID:20471948</ref> <ref>PMID:20159561</ref> <ref>PMID:23251033</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+As approximately 70% of human breast tumors are estrogen receptor alpha (ERalpha)-positive, estrogen and ERalpha play essential roles in breast cancer development. By interrupting the ERalpha signaling pathway, endocrine therapy has been proven to be an effective therapeutic strategy. In this study, we identified a mechanism by which Transcription Start Site (TSS)-associated histone H3K27 acetylation signals the Super Elongation Complex (SEC) to regulate transcriptional elongation of the ESR1 (ERalpha) gene. SEC interacts with H3K27ac on ESR1 TSS through its scaffold protein AFF4. Depletion of AFF4 by siRNA or CRISPR/Cas9 dramatically reduces expression of ESR1 and its target genes, consequently inhibiting breast cancer cell growth. More importantly, a AFF4 mutant which lacks H3K27ac interaction failed to rescue ESR1 gene expression, suggesting H3K27 acetylation at TSS region is a key mark bridging the transition from transcriptional initiation to elongation, and perturbing SEC function can be an alternative strategy for targeting ERalpha signaling pathway at chromatin level.
+Acetylation of histone H3K27 signals the transcriptional elongation for estrogen receptor alpha.,Gao Y, Chen L, Han Y, Wu F, Yang WS, Zhang Z, Huo T, Zhu Y, Yu C, Kim H, Lee M, Tang Z, Phillips K, He B, Jung SY, Song Y, Zhu B, Xu RM, Feng Q Commun Biol. 2020 Apr 7;3(1):165. doi: 10.1038/s42003-020-0898-0. PMID:32265480<ref>PMID:32265480</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6kn5" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Chen LJ]]
+[[Category: Chen, L J]]
-[[Category: Xu RM]]
+[[Category: Xu, R M]]
-[[Category: Yang WS]]
+[[Category: Yang, W S]]
+[[Category: Aff4]]
+[[Category: Histone acetylation]]
+[[Category: Transcription]]

6kn5

From Proteopedia

Revision as of 11:44, 23 March 2022

Crystal structure of AFF4 C-terminal domain

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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