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Elife. 2013 Mar 5;2:e00327. doi: 10.7554/eLife.00327.

The AFF4 scaffold binds human P-TEFb adjacent to HIV Tat.

Author information

1
Department of Molecular and Cell Biology , University of California, Berkeley , Berkeley , United States.

Abstract

Human positive transcription elongation factor b (P-TEFb) phosphorylates RNA polymerase II and regulatory proteins to trigger elongation of many gene transcripts. The HIV-1 Tat protein selectively recruits P-TEFb as part of a super elongation complex (SEC) organized on a flexible AFF1 or AFF4 scaffold. To understand this specificity and determine if scaffold binding alters P-TEFb conformation, we determined the structure of a tripartite complex containing the recognition regions of P-TEFb and AFF4. AFF4 meanders over the surface of the P-TEFb cyclin T1 (CycT1) subunit but makes no stable contacts with the CDK9 kinase subunit. Interface mutations reduced CycT1 binding and AFF4-dependent transcription. AFF4 is positioned to make unexpected direct contacts with HIV Tat, and Tat enhances P-TEFb affinity for AFF4. These studies define the mechanism of scaffold recognition by P-TEFb and reveal an unanticipated intersubunit pocket on the AFF4 SEC that potentially represents a target for therapeutic intervention against HIV/AIDS. DOI:http://dx.doi.org/10.7554/eLife.00327.001.

KEYWORDS:

Human; SEC; intrinsically disordered proteins; super elongation complex; transcription elongation

PMID:
23471103
PMCID:
PMC3589825
DOI:
10.7554/eLife.00327
[Indexed for MEDLINE]
Free PMC Article
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