Directed Blocking of TGF-ß Receptor I Binding Site Using Tailored Peptide Segments to Inhibit its Signaling Pathway.
Iran J Biotechnol
; 18(1): e2561, 2020 Jan.
Article
en En
| MEDLINE
| ID: mdl-32884960
ABSTRACT
BACKGROUND:
TGF-ß isoforms play crucial roles in diverse cellular processes. Therefore, targeting and inhibiting TGF-ß signaling pathway provides a potential therapeutic opportunity. TGF-ß isoforms bind and bring the receptors (TßRII and TßRI) together to form a signaling complex in an ordered manner.OBJECTIVES:
Herein, an antagonistic variant of TGF-ß (AnTß) has been designed and prepared to inhibit the formation of signaling complex and consequently its signaling pathway. This TGF-ß homodimeric variant contains intact TßRII binding sites and blocked TßRI binding sites by substituting three peptide segments. So, AnTß could only bind to TßRII, but prevent binding and recruitment of TßRI to form a signaling complex. MATERIALS ANDMETHODS:
A reliable model of AnTß was built and reï¬ned using molecular dynamics (MD) simulation, followed by investigating the interactions of AnTß with the receptors using in silico docking studies. After expression of disulfide-linked AnTß in a SHuffle strain and purification of the protein using affinity chromatography, its biological activity was evaluated using Mink lung epithelial cells (Mvl Lu).RESULTS:
No meaningful significant changes in AnTß structure were observed when compared with the native protein. Based on the docking analysis, AnTß binds to TßRII similar to TGF-ß and its binding to TßRI was diminished considerably which was consistent with our design purpose. Cell-based bioassay indicated that AnTß could modulate TGF-ß-induced cell growth inhibition.CONCLUSIONS:
Our analysis suggests that the antagonistic potency of AnTß can be used as an anti-TGFß signaling factor in the future perspectives.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Iran J Biotechnol
Año:
2020
Tipo del documento:
Article
País de afiliación:
Irán