Structure‐based discovery and redesign of TGF‐β1 Elbow epitope recognition by its type‐II receptor in hypertrophic scarring biotherapy. Issue 4 (2nd November 2020)

• Record Type: Journal Article
• Authors: Chen, Xiaoting; Wang, Huixiong; Yang, Songlin; Zheng, Jianghong; Liu, Xiangdong; Mao, Guangyu
• Is Part Of: Journal of molecular recognition. Volume 34:Issue 4(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-11-02
• Subjects: biomolecular recognition -- biotherapy -- elbow epitope -- hypertrophic scarring -- peptide -- TGF‐β1 signaling pathway -- type‐II receptor; Molecular recognition -- Periodicals; Models, Molecular -- Periodicals; Molecular Conformation -- Periodicals; Molecular Sequence Data -- Periodicals; Molecular Structure -- Periodicals; Carrier Proteins -- Periodicals; 572.8
• DOI: 10.1002/jmr.2881
• Languages: English
• ISSNs: 0952-3499

Abstract

Abstract: Transforming growth factor‐β1 (TGF‐β1) signaling pathway has been implicated in the fibroblast activation of hypertrophic scarring (HS). Previously, we proposed a new biotherapeutic strategy to combat HS by disrupting the intermolecular interaction of TGF‐β1 with its cognate type‐II receptor (TβR‐II). Here, we further demonstrate that the binding site of TGF‐β1 to TβR‐II is not overlapped with the conformational wrist epitope and linear knuckle epitope that are traditionally recognized as the functional binding sites of bone morphogenetic protein‐2 (BMP‐2) to its type‐II receptor (BMPR‐II), which can thus be regarded as a new functional site we called elbow epitope. Structural, energetic, and dynamic investigations reveal that the elbow epitope consists of two sequentially discontinuous, spatially vicinal segments Loop 30‐34 and Turn 90‐95 ; they cannot work effectively to independently interact with TβR‐II. Rational redesign of the epitope is performed using an integrated in silio‐in vitro method based on crystal and modeled structure data. In the procedure, the two epitope segments are split from the interface of TGF‐β1‐TβR‐II complex and then connected with each other in a head‐to‐tail manner by adding a flexible poly‐(Gly) n linker between them, thus resulting in a series of combined peptides. We found that the peptide affinity reaches maximum at n = 2, which shares a consistent binding mode with the elbow epitope at native complex interface. The linker of either too long (n > 2) or too short (n < 2) cannot properly place the gap space between the two segments, thus impairing the binding compatibility of designed peptides with TβR‐II active site.