Format

Send to

Choose Destination
Cell Rep. 2018 Mar 20;22(12):3251-3264. doi: 10.1016/j.celrep.2018.02.097.

Gcn4-Mediator Specificity Is Mediated by a Large and Dynamic Fuzzy Protein-Protein Complex.

Author information

1
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
2
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
3
The Institute for Systems Biology, Seattle, WA 98109, USA.
4
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Electronic address: shahn@fredhutch.org.
5
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. Electronic address: klevit@u.washington.edu.

Abstract

Transcription activation domains (ADs) are inherently disordered proteins that often target multiple coactivator complexes, but the specificity of these interactions is not understood. Efficient transcription activation by yeast Gcn4 requires its tandem ADs and four activator-binding domains (ABDs) on its target, the Mediator subunit Med15. Multiple ABDs are a common feature of coactivator complexes. We find that the large Gcn4-Med15 complex is heterogeneous and contains nearly all possible AD-ABD interactions. Gcn4-Med15 forms via a dynamic fuzzy protein-protein interface, where ADs bind the ABDs in multiple orientations via hydrophobic regions that gain helicity. This combinatorial mechanism allows individual low-affinity and specificity interactions to generate a biologically functional, specific, and higher affinity complex despite lacking a defined protein-protein interface. This binding strategy is likely representative of many activators that target multiple coactivators, as it allows great flexibility in combinations of activators that can cooperate to regulate genes with variable coactivator requirements.

KEYWORDS:

fuzzy binding; intrinsically disordered proteins; transcription activation

PMID:
29562181
PMCID:
PMC5908246
DOI:
10.1016/j.celrep.2018.02.097
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center