A Potential Structural Switch for Regulating DNA-Binding by TEAD Transcription Factors.

Area of Science:

• Molecular Biology
• Structural Biology
• Biochemistry

Background:

• TEA domain (TEAD) transcription factors are crucial for eukaryotic development and downstream effectors of the Hippo pathway.
• Previous studies determined the structure of the TEAD DNA-binding domain (DBD) but lacked insight into regulatory mechanisms.
• The structural basis for regulating TEAD DNA-binding activity remained unelucidated.

Purpose of the Study:

• To investigate the structural basis of TEAD transcription factor DNA-binding regulation.
• To characterize a mutant TEAD DBD with a truncated L1 loop (ΔL1 TEAD DBD).
• To elucidate the role of the L1 loop in TEAD DNA-binding activity and selectivity.

Main Methods:

• X-ray crystallography was employed to determine the three-dimensional structure of the ΔL1 TEAD DBD.
• Biochemical assays were conducted to assess the DNA-binding activity of the mutant.
• Structural homology comparisons were made with known protein domains.

Main Results:

• The ΔL1 TEAD DBD unexpectedly formed a helix-swapped homodimer, with helix 1 swapped between monomers.
• Each three-helix bundle in the dimer showed homology to MYB-like domains.
• While the ΔL1 TEAD DBD could bind isolated DNA elements, it exhibited deficient cooperative binding to duplicated elements, highlighting the L1 loop's importance.

Conclusions:

• The L1 loop is critical for the cooperative DNA-binding activity of TEAD transcription factors.
• The formation of domain-swapped dimeric forms of TEAD may regulate DNA binding selectivity.
• Structural plasticity, including domain swapping, could be a key mechanism for controlling TEAD function in biological processes.