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

Dingwa Zhang, Deyong He, Xiaoliang Pan, Lijun Liu

Protein and peptide letters 2020

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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. 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. 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. 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). 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. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.

Citation

Dingwa Zhang, Deyong He, Xiaoliang Pan, Lijun Liu. Rational Design and Intramolecular Cyclization of Hotspot Peptide Segments at YAP-TEAD4 Complex Interface. Protein and peptide letters. 2020;27(10):999-1006