Rational Design and Intramolecular Cyclization of Hotspot Peptide Segments at YAP–TEAD4 Complex Interface

Dingwa       Zhang; Deyong       He; Xiaoliang       Pan; Lijun       Liu

doi:10.2174/0929866527666200414160723

Abstract

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: We systematically examine the crystal structure of YAP complex with TEAD4 and rationally identify two hotspot segments at the complex interface; they could be exploited as self-inhibitory peptides to target the complex interaction.

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 (K_d = 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 (K_d = 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.

Keywords: Yes-associated protein, peptide, intramolecular cyclization, rational peptide design, protein-protein interaction, cancer therapy.

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DOI https://dx.doi.org/10.2174/0929866527666200414160723	Print ISSN 0929-8665
Publisher Name Bentham Science Publisher	Online ISSN 1875-5305

Protein & Peptide Letters

Rational Design and Intramolecular Cyclization of Hotspot Peptide Segments at YAP–TEAD4 Complex Interface

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