VGLL4-driven TEAD4 multimerization orchestrates DNA binding and YAP recruitment

Area of Science:

• Molecular Biology
• Cell Signaling
• Biophysics

Background:

• The Hippo pathway regulates organ size and tissue homeostasis.
• TEAD transcription factors are key downstream effectors, interacting with cofactors like YAP/TAZ and VGLL proteins.
• Understanding TEAD-DNA interactions is crucial for deciphering gene regulation.

Purpose of the Study:

• To investigate the DNA binding dynamics of TEAD4.
• To explore the role of TEAD4 multimerization in DNA binding and YAP recruitment.
• To elucidate the stoichiometry-dependent effect of VGLL4 on TEAD4-YAP interactions.

Main Methods:

• Fluorescence-combined optical tweezers to measure DNA binding kinetics.
• Analysis of TEAD4 monomeric and multimeric DNA binding.
• Investigating the influence of YAP and VGLL4 on TEAD4 multimerization and DNA binding.

Main Results:

• Monomeric TEAD4 exhibits fast dissociation from DNA, while multimerization enhances DNA residence time and YAP recruitment.
• Both YAP and VGLL4 promote TEAD4 multimerization, strengthening DNA binding and specificity.
• VGLL4's Tondu domains show a stoichiometry-dependent effect on YAP recruitment, enhancing it at low ratios and inhibiting at high ratios.

Conclusions:

• TEAD4 DNA binding is dynamic, with multimerization significantly altering its interaction with DNA.
• VGLL4 acts as a crucial regulator of TEAD4-mediated YAP recruitment in a concentration-dependent manner.
• This study reveals a novel molecular mechanism for VGLL4 in modulating Hippo pathway signaling.