A new perspective on the interaction between the Vg/VGLL1-3 proteins and the TEAD transcription factors

Abstract

The most downstream elements of the Hippo pathway, the TEAD transcription factors, are regulated by several cofactors, such as Vg/VGLL1-3. Earlier findings on human VGLL1 and here on human VGLL3 show that these proteins interact with TEAD via a conserved amino acid motif called the TONDU domain. Surprisingly, our studies reveal that the TEAD-binding domain of Drosophila Vg and of human VGLL2 is more complex and contains an additional structural element, an Ω-loop, that contributes to TEAD binding. To explain this unexpected structural difference between proteins from the same family, we propose that, after the genome-wide duplications at the origin of vertebrates, the Ω-loop present in an ancestral VGLL gene has been lost in some VGLL variants. These findings illustrate how structural and functional constraints can guide the evolution of transcriptional cofactors to preserve their ability to compete with other cofactors for binding to transcription factors.

Biochemical properties of VGLL4 from Homo sapiens and Tgi from Drosophila melanogaster and possible biological implications

“…In VGLL1, an arginine residue located two amino acids after the phenylalanine of the Φ‐D/E‐D/E‐H‐F motif makes an important π‐cation interaction with a phenylalanine from TEAD 17 . Since a similar interaction is observed in the Vg:Sd complex, 15 but also between Lys240 VGLL4 and Phe330 TEAD in the VGLL4:TEAD complex (Figure 1), 18 we looked for the presence of an arginine/lysine at this position in each sequence. These charged residues are present in all sequences identified in the BLASTp search, and interestingly an arginine is always found after the Φ‐D/E‐D/E‐H‐F motif in the region corresponding to helix‐1, while this is a lysine in the region corresponding to helix‐2 (Figure S2).…”

“…Affinities for TEAD4 and Sd. (a) The amino acid sequence of the peptides and the secondary structure they adopt in their bound conformation are indicated (VGLL1 from PDB 5z2q; 11 Vg from PDB 6y20; 15 VGLL4 from PDB 4ln0 18 ‐ α1‐3: correspond to helix‐1‐3). The peptide sequences are from human VGLL1 UniProtKB Q99990; human VGLL2 UniProtKB Q8N8G2; human VGLL4 UniProtKB Q14135; Drosophila melanogaster Vg UniProtKB Q26366 and D. melanogaster Tgi UniProtKB Q8IQJ9.…”

“…The values are the averages and the standard errors of n ≥ 2 experiments. a. K d taken from 14 and b K d taken from 15 . (b) The affinities of VGLL4/Tgi for TEAD4/Sd immobilized at low and high levels are indicated.…”

“…The “hot spot” for the interaction with TEAD is the Ω‐loop in YAP/TAZ and the α‐helix in VGLL1 10,11,13,14 . Recently, it has been found that the Sd/TEAD‐binding domain of Vg and VGLL2 contains a β‐strand:α‐helix region, but also an Ω‐loop 15 . The α‐helix from the TEAD/Sd‐binding domain of VGLL1/Vg contains an amino acid motif, Φ‐D/E‐D/E‐H‐F (Φ hydrophobic residue), that is characteristic for this protein family 5 .…”

Protein-Protein Interaction Disruptors of the YAP/TAZ-TEAD Transcriptional Complex

“…Recently, a tertiary structure mimetic of VGLL4 was used as a PPID to disrupt the interaction between TEAD and VGLL4 [ 48 ]. VGLL proteins (VGLL1-4 in humans) are another class of TEAD-binding co-regulators that mimic YAP/TAZ by forming structurally similar interfaces [ 14 , 49 , 50 ]. As an alternate strategy, residues of YAP/VGLL interface 3 can be coupled to interface 2 as coupling interface 3 residues contributes to a 400-fold increase in potency [ 13 ].…”