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Forkhead Domains of FOXO Transcription Factors Differ in both Overall Conformation and Dynamics
Katarina Psenakova1,2, Klara Kohoutova1, Veronika Obsilova2
1Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, 128 43 Prague, Czech Republic.
Abstract:
FOXO transcription factors regulate cellular homeostasis, longevity and response to stress. FOXO1 (also known as FKHR) is a key regulator of hepatic glucose production and lipid metabolism, and its specific inhibition may have beneficial effects on diabetic hyperglycemia by reducing hepatic glucose production. Moreover, all FOXO proteins are considered potential drug targets for drug resistance prevention in cancer therapy. However, the development of specific FOXO inhibitors requires a detailed understanding of structural differences between individual FOXO DNA-binding domains. The high-resolution structure of the DNA-binding domain of FOXO1 reported in this study and its comparison with structures of other FOXO proteins revealed differences in both their conformation and flexibility. These differences are encoded by variations in protein sequences and account for the distinct functions of FOXO proteins. In particular, the positions of the helices H1, H2 and H3, whose interface form the hydrophobic core of the Forkhead domain, and the interactions between hydrophobic residues located on the interface between the N-terminal segment, the H2-H3 loop, and the recognition helix H3 differ among apo FOXO1, FOXO3 and FOXO4 proteins. Therefore, the availability of apo structures of DNA-binding domains of all three major FOXO proteins will support the development of FOXO-type-specific inhibitors.
Insights
Understanding structural differences in FOXO proteins is key for developing targeted therapies. This study reveals distinct conformations and flexibility in FOXO DNA-binding domains, aiding the creation of specific FOXO inhibitors for diabetes and cancer.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Forkhead box O (FOXO) transcription factors are crucial for cellular homeostasis, longevity, and stress response.
- FOXO1 specifically regulates hepatic glucose and lipid metabolism, making it a target for diabetic hyperglycemia.
- FOXO proteins are also implicated in cancer therapy and drug resistance prevention.
Purpose of the Study:
- To determine the high-resolution structure of the FOXO1 DNA-binding domain.
- To compare the structural features of FOXO1 with other FOXO proteins (FOXO3, FOXO4).
- To elucidate how structural variations contribute to distinct FOXO protein functions and inform the development of specific inhibitors.
Main Methods:
- High-resolution structural determination of the FOXO1 DNA-binding domain.
- Comparative structural analysis of apo FOXO1, FOXO3, and FOXO4 DNA-binding domains.
- Analysis of protein sequence variations and their impact on protein conformation and flexibility.
Main Results:
- The study reports the high-resolution structure of the FOXO1 DNA-binding domain.
- Significant differences in conformation and flexibility were observed between FOXO1, FOXO3, and FOXO4 DNA-binding domains.
- These structural variations are linked to sequence differences and distinct protein functions, particularly in the hydrophobic core and interfacial interactions of the Forkhead domain.
Conclusions:
- Structural insights into FOXO DNA-binding domains reveal sequence-encoded variations in conformation and flexibility.
- Understanding these differences is essential for designing FOXO-type-specific inhibitors.
- The availability of apo structures for major FOXO proteins will facilitate the development of targeted therapeutic strategies for metabolic diseases and cancer.
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