Background:
The Yes-Associated Protein (YAP) is a central regulator of Hippo pathway
involved in carcinogenesis, which functions through interaction with TEA Domain (TEAD)
transcription factors. Pharmacological disruption of YAP–TEAD4 complexes has been recognized
as a potential therapeutic strategy against diverse cancers by suppressing the oncogenic activity of
YAP.
Objective:
Two peptides, termed PS-1 and PS-2 are split from the interfacial context of YAP protein.
Dynamics simulations, energetics analyses and fluorescence polarizations are employed to
characterize the intrinsic disorder as well as binding energy/affinity of the two YAP peptides to
TEAD4 protein.
Methods:
Two peptides, termed PS-1 and PS-2 are split from the interfacial context of YAP protein.
Dynamics simulations, energetics analyses and fluorescence polarizations are employed to
characterize the intrinsic disorder as well as binding energy/affinity of the two YAP peptides to
TEAD4 protein.
Result:
The native conformation of PS-2 peptide is a cyclic loop, which is supposed to be constrained
by adding a disulfide bond across the spatially vicinal residue pair Arg87-Phe96 or Met86-
Phe95 at the peptide’s two ends, consequently resulting in two intramolecular cyclized counterparts
of linear PS-2 peptide, namely PS-2(cyc87,96) and PS-2(cyc86,95). The linear PS-2 peptide
is determined as a weak binder of TEAD4 (Kd = 190 μM), while the two cyclic PS-2(cyc87,96) and
PS-2(cyc86,95) peptides are measured to have moderate or high affinity towards TEAD4 (Kd = 21
and 45 μM, respectively).
Conclusion:
PS-1 and PS-2 peptides are highly flexible and cannot maintain in native active conformation
when splitting from the interfacial context, and thus would incur a considerable entropy
penalty upon rebinding to the interface. Cyclization does not influence the direct interaction between
PS-2 peptide and TEAD4 protein, but can largely reduce the intrinsic disorder of PS-2 peptide
in free state and considerably minimize indirect entropy effect upon the peptide binding.