6r80

From Proteopedia

(Difference between revisions)

Revision as of 05:50, 12 June 2019

Structure of AFF4 C-terminal homology domain

Structural highlights

6r80 is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
NonStd Res:
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

AF4/FMR2 family member 4 (AFF4) is the scaffold protein of the multi-subunit super-elongation complex (SEC), which plays key roles in the release of RNA polymerase (Pol) II from promoter-proximal pausing and in the transactivation of HIV-1 transcription. AFF4 consists of an intrinsically disordered N-terminal region that interacts with other SEC subunits and a C-terminal homology domain (CHD) that is conserved among AF4/FMR2 family proteins, including AFF1, AFF2, AFF3, and AFF4. Here, we solved the X-ray crystal structure of the CHD in human AFF4 (AFF4-CHD) to 2.2 A resolution and characterized its biochemical properties. The structure disclosed that AFF4-CHD folds into a novel domain that consists of eight helices and is distantly related to tetratrico peptide repeat (TPR) motifs. Our analyses further revealed that AFF4-CHD mediates the formation of an AFF4 homodimer or an AFF1-AFF4 heterodimer. Results from fluorescence anisotropy experiments suggested that AFF4-CHD interacts with both RNA and DNA in vitro. Furthermore, we identified a surface loop region in AFF4-CHD as a substrate for the P-TEFb kinase cyclin-dependent kinase 9 (CDK9), which triggers release of Pol II from promoter-proximal pausing sites. In conclusion, the AFF-CHD structure and biochemical analyses reported here reveal the molecular basis for the homo- and heterodimerization of AFF proteins and implicate the AFF4-CHD in nucleic acid interactions. The high conservation of the CHD among several other proteins suggests that our results are relevant also for understanding other CHD-containing proteins and their dimerization behavior.

Structure of the super-elongation complex subunit AFF4 C-terminal homology domain reveals requirements for AFF homo- and heterodimerization.,Chen Y, Cramer P J Biol Chem. 2019 May 30. pii: RA119.008577. doi: 10.1074/jbc.RA119.008577. PMID:31147444^[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
↑ Chen Y, Cramer P. Structure of the super-elongation complex subunit AFF4 C-terminal homology domain reveals requirements for AFF homo- and heterodimerization. J Biol Chem. 2019 May 30. pii: RA119.008577. doi: 10.1074/jbc.RA119.008577. PMID:31147444 doi:http://dx.doi.org/10.1074/jbc.RA119.008577

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/6r80"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6r80 is ON HOLD  until Paper Publication
+==Structure of AFF4 C-terminal homology domain==
+<StructureSection load='6r80' size='340' side='right'caption='[[6r80]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6r80]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6R80 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6R80 FirstGlance]. <br>
+</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></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=6r80 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r80 OCA], [http://pdbe.org/6r80 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6r80 RCSB], [http://www.ebi.ac.uk/pdbsum/6r80 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6r80 ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[[http://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 ==
+[[http://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 ==
+AF4/FMR2 family member 4 (AFF4) is the scaffold protein of the multi-subunit super-elongation complex (SEC), which plays key roles in the release of RNA polymerase (Pol) II from promoter-proximal pausing and in the transactivation of HIV-1 transcription. AFF4 consists of an intrinsically disordered N-terminal region that interacts with other SEC subunits and a C-terminal homology domain (CHD) that is conserved among AF4/FMR2 family proteins, including AFF1, AFF2, AFF3, and AFF4. Here, we solved the X-ray crystal structure of the CHD in human AFF4 (AFF4-CHD) to 2.2 A resolution and characterized its biochemical properties. The structure disclosed that AFF4-CHD folds into a novel domain that consists of eight helices and is distantly related to tetratrico peptide repeat (TPR) motifs. Our analyses further revealed that AFF4-CHD mediates the formation of an AFF4 homodimer or an AFF1-AFF4 heterodimer. Results from fluorescence anisotropy experiments suggested that AFF4-CHD interacts with both RNA and DNA in vitro. Furthermore, we identified a surface loop region in AFF4-CHD as a substrate for the P-TEFb kinase cyclin-dependent kinase 9 (CDK9), which triggers release of Pol II from promoter-proximal pausing sites. In conclusion, the AFF-CHD structure and biochemical analyses reported here reveal the molecular basis for the homo- and heterodimerization of AFF proteins and implicate the AFF4-CHD in nucleic acid interactions. The high conservation of the CHD among several other proteins suggests that our results are relevant also for understanding other CHD-containing proteins and their dimerization behavior.
-Authors:
+Structure of the super-elongation complex subunit AFF4 C-terminal homology domain reveals requirements for AFF homo- and heterodimerization.,Chen Y, Cramer P J Biol Chem. 2019 May 30. pii: RA119.008577. doi: 10.1074/jbc.RA119.008577. PMID:31147444<ref>PMID:31147444</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 6r80" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Large Structures]]
+[[Category: Chen, Y]]
+[[Category: Cramer, P]]
+[[Category: Dimerisation domain]]
+[[Category: Transcription]]
+[[Category: Transcription elongation factor]]

6r80

From Proteopedia

Revision as of 05:50, 12 June 2019

Structure of AFF4 C-terminal homology domain

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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