Multivalency regulates activity in an intrinsically disordered transcription factor.

Area of Science:

• Molecular Biology
• Biochemistry
• Genetics

Background:

• The transcription factor ASCIZ (ATMIN, ZNF822) interacts with the hub protein LC8 (DYNLL1).
• ASCIZ possesses multiple binding sites for LC8, suggesting complex regulatory roles.

Purpose of the Study:

• To elucidate the mechanism by which ASCIZ regulates transcription through its interaction with LC8.
• To investigate the role of intrinsic disorder and multivalency in ASCIZ-LC8 complex formation and function.

Main Methods:

• Biophysical methods
• Nuclear Magnetic Resonance (NMR) and electron microscopy for structural analysis
• Cellular transcription assays

Main Results:

• ASCIZ's intrinsically disordered C-terminal domain binds LC8, forming a dynamic ensemble of complexes.
• Transcriptional activity is inversely proportional to LC8 occupancy, indicating negative cooperativity.
• Both human and Drosophila ASCIZ show a preference for low LC8 occupancy complexes.

Conclusions:

• Intrinsic disorder and multiple binding events are key to ASCIZ's regulation of LC8 transcription.
• Negative cooperativity in ASCIZ-LC8 interactions is crucial for tuning transcriptional output.
• Heterogeneous, dynamic complex formation is a common strategy for transcriptional regulation by transcription factors.