Correlating disordered activation domain ensembles with gene expression levels

Area of Science:

• Molecular Biology
• Biochemistry
• Genetics

Background:

• Transcription factors regulate gene expression by binding DNA.
• Intrinsically disordered activation domains (ADs) lack fixed structures and exist as conformational ensembles.
• Disordered protein regions often have sequence-encoded structural preferences linked to function.

Purpose of the Study:

• To investigate the link between the structural preferences of AD ensembles and their transcriptional activity.
• To determine if AD ensemble dimensions correlate with their ability to induce gene expression.

Main Methods:

• Measured ensemble dimensions of two ADs (HIF-1α and CITED2) in live cells using fluorescence resonance energy transfer (FRET) microscopy.
• Correlated structural ensemble data with transcriptional activity measurements.

Main Results:

• Mutations expanding the HIF-1α AD ensemble increased transcriptional activity.
• Mutations compacting the HIF-1α AD ensemble reduced transcriptional activity.
• No correlation was found between ensemble dimensions and activity for CITED2 AD.

Conclusions:

• AD structural plasticity is critical for regulating HIF-1α function.
• A link between AD ensemble dimensions and transcriptional activity may exist for some proteins.
• Findings have implications for understanding transcriptional regulation and dysfunction.