Structural and functional similarity between the Vgll1-TEAD and the YAP-TEAD complexes

Area of Science:

• Molecular Biology
• Structural Biology
• Cancer Research

Background:

• The Hippo signaling pathway regulates organ size and cell proliferation through the YAP/TAZ-TEAD transcriptional complex.
• Understanding the structural basis of TEAD transcription factor interactions is crucial for deciphering gene regulation.
• Vgll1, a vestigial-like protein, is structurally related to transcriptional coactivators but its functional role with TEADs is less understood.

Purpose of the Study:

• To determine the crystal structure of the Vgll1-TEAD4 complex.
• To compare the interaction mode of Vgll1 with TEAD4 to that of YAP/TAZ with TEADs.
• To investigate the functional consequences of Vgll1-TEAD complex formation on gene expression and cell proliferation.

Main Methods:

• X-ray crystallography to determine the Vgll1-TEAD4 complex structure.
• Biochemical assays to assess protein-protein interactions.
• Gene expression analysis (e.g., RT-qPCR) to measure target gene upregulation.
• Cell proliferation assays (e.g., soft agar) to evaluate anchorage-independent growth.

Main Results:

• The Vgll1-TEAD4 complex structure reveals a conserved binding interface similar to YAP/TAZ-TEAD complexes, despite sequence divergence.
• Vgll1 binding to TEAD4 upregulates the expression of IGFBP-5, a gene associated with proliferation.
• The Vgll1-TEAD4 complex promotes anchorage-independent cell proliferation, a hallmark of cancer.

Conclusions:

• Vgll1 acts as a functional homolog of YAP/TAZ in complex with TEAD4.
• The structural and functional similarities suggest Vgll1 could contribute to oncogenesis.
• Targeting the Vgll1-TEAD interaction may offer therapeutic strategies for cancers driven by this pathway.