Structural Insight into the Binding of TGIF1 to SIN3A PAH2 Domain through a C-Terminal Amphipathic Helix

• Published in: International journal of molecular sciences Vol. 22; no. 23; p. 12631
• Main Authors: He, Xiaoling, Nie, Yao, Zhou, Heng, Hu, Rui, Li, Ying, He, Ting, Zhu, Jiang, Yang, Yunhuang, Liu, Maili
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 23-11-2021; MDPI
• Subjects: Binding; Binding Sites; Circular Dichroism; Dimerization; Domains; Gene silencing; Genes; HeLa Cells; Holoprosencephaly; Homeodomain Proteins - chemistry; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Homology; Humans; Hydrophobicity; intrinsically disordered protein; Models, Molecular; molecular modeling; Mutation; nuclear magnetic resonance (NMR); Peptide inhibitors; Protein Binding; Protein Domains; Protein Structure, Secondary; protein–protein interaction; Repressor Proteins - chemistry; Repressor Proteins - genetics; Repressor Proteins - metabolism; Residues; Scattering, Small Angle; Sin3 Histone Deacetylase and Corepressor Complex - chemistry; Sin3 Histone Deacetylase and Corepressor Complex - genetics; Sin3 Histone Deacetylase and Corepressor Complex - metabolism; Spectrum analysis; Structure-function relationships; transcription repressor; Yeast; protein–protein interaction; transcription repressor; intrinsically disordered protein; molecular modeling; nuclear magnetic resonance (NMR)
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms222312631

TGIF1 is a transcriptional repressor playing crucial roles in human development and function and is associated with holoprosencephaly and various cancers. TGIF1-directed transcriptional repression of specific genes depends on the recruitment of corepressor SIN3A. However, to date, the exact region of TGIF1 binding to SIN3A was not clear, and the structural basis for the binding was unknown. Here, we demonstrate that TGIF1 utilizes a C-terminal domain (termed as SIN3A-interacting domain, SID) to bind with SIN3A PAH2. The TGIF1 SID adopts a disordered structure at the apo state but forms an amphipathic helix binding into the hydrophobic cleft of SIN3A PAH2 through the nonpolar side at the holo state. Residues F379, L382 and V383 of TGIF1 buried in the hydrophobic core of the complex are critical for the binding. Moreover, homodimerization of TGIF1 through the SID and key residues of F379, L382 and V383 was evidenced, which suggests a dual role of TGIF1 SID and a correlation between dimerization and SIN3A-PAH2 binding. This study provides a structural insight into the binding of TGIF1 with SIN3A, improves the knowledge of the structure-function relationship of TGIF1 and its homologs and will help in recognizing an undiscovered SIN3A-PAH2 binder and developing a peptide inhibitor for cancer treatment.