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  Structure of the super-elongation complex subunit AFF4 C-terminal homology domain reveals requirements for AFF homo- and heterodimerization.

Chen, Y., & Cramer, P. (2019). Structure of the super-elongation complex subunit AFF4 C-terminal homology domain reveals requirements for AFF homo- and heterodimerization. Journal of Biological Chemistry, 294, 10663-10673. doi:10.1074/jbc.RA119.008577.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-B33A-2 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-FE3C-D
Genre: Journal Article

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Chen, Y., Author
Cramer, P.1, Author              
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1Department of Molecular Biology, MPI for Biophysical Chemistry, Max Planck Society, ou_1863498              

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Free keywords: AF4/FMR2 family member 4 (AFF4); C-terminal homology domain (CHD); RNA polymerase II; X-ray crystallography; dimerization; gene regulation; phosphorylation; super elongation complex; transcription elongation factor
 Abstract: 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 Å 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.

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Language(s): eng - English
 Dates: 2019-05-302019-07-05
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1074/jbc.RA119.008577
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Title: Journal of Biological Chemistry
Source Genre: Journal
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Pages: - Volume / Issue: 294 Sequence Number: - Start / End Page: 10663 - 10673 Identifier: -