FC0094
AF4 elongation factor  -  AF9 AHD

Biological function
Regulator of RNA polymerase II-mediated transcription through elongation and chromatin remodeling functions.

Domain organization/sequence features
N-terminal homology domain, an AF4/ lymphoid nuclear protein related to AF4/Fragile X E mental retardation syndrome domain, and a C-terminal homology domain.

Structural evidence
In the crystal structure of the complex with AF9 AHD only 761-775 AA segment of AF4 become ordered, the preceding region remains to be dynamic. The contacting region 761-767 also exhibits considerable dynamics in the bound state based on ¹⁵N backbone relaxation measurements. These have a low R1*R2, suggesting ns/ps dynamics in the backbone, and which likely reflect rotameric averaging and methyl dynamics in the core, visible in the NOESY data.

Biochemical evidence
The affinity for AF4 is extremely high with K_D = 0.17 ± 0.05 nM. Linear motif interactions normally have affinities in the μM-mM range, at least three orders of magnitude lower than AF4. This indicates that the interaction involves those residues, which do not become ordered upon binding.

Structure/Mechanism
AF4 is very sensitive to proteosomal degradation. Avidity of interactions with AF9 thus strongly influence its lifetime.

Mechanism category
tethering, flexibility modulation

Posttranslational modification
AF4 contain phosphorylation sites within the AF9 consensus binding sequence, which may allow transient and reversible regulation of these interactions. For instance, phosphorylation of T766 of AF4 results in an ~ 30-fold reduction of its affinity for AF9.

Significance
Fuzziness is important for regulation of developmentally critical genes which must be turned on or off with high fidelity, but in a rapid and synchronous manner.

Submitted by
John Bushweller   jhb4v@virginia.edu, bileach@scripps.edu