The prolyl isomerase FKBP25 regulates microtubule polymerization impacting cell cycle progression and genomic
David Dilworth1, Geoff Gudavicius1, Xiaoxue Xu2
1Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, V8W 3P6, Canada.
Abstract:
FK506 binding proteins (FKBPs) catalyze the interconversion of cis-trans proline conformers in proteins. Importantly, FK506 drugs have anti-cancer and neuroprotective properties, but the effectors and mechanisms underpinning these properties are not well understood because the cellular function(s) of most FKBP proteins are unclear. FKBP25 is a nuclear prolyl isomerase that interacts directly with nucleic acids and is associated with several DNA/RNA binding proteins. Here, we show the catalytic FKBP domain binds microtubules (MTs) directly to promote their polymerization and stabilize the MT network. Furthermore, FKBP25 associates with the mitotic spindle and regulates entry into mitosis. This interaction is important for mitotic spindle dynamics, as we observe increased chromosome instability in FKBP25 knockdown cells. Finally, we provide evidence that FKBP25 association with chromatin is cell-cycle regulated by Protein Kinase C phosphorylation. This disrupts FKBP25-DNA contacts during mitosis while maintaining its interaction with the spindle apparatus. Collectively, these data support a model where FKBP25 association with chromatin and MTs is carefully choreographed to ensure faithful genome duplication. Additionally, they highlight that FKBP25 is a MT-associated FK506 receptor and potential therapeutic target in MT-associated diseases.
Insights
FKBP25 protein binds microtubules, promoting polymerization and stabilizing the cell
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- FK506 binding proteins (FKBPs) are crucial for protein folding and cellular processes.
- The precise functions of most FKBPs, including FKBP25, remain largely unknown.
- FK506 drugs exhibit therapeutic potential in cancer and neuroprotection, necessitating a deeper understanding of FKBP mechanisms.
Purpose of the Study:
- To elucidate the cellular functions and molecular mechanisms of FKBP25.
- To investigate FKBP25's role in microtubule dynamics and cell division.
- To explore FKBP25 as a potential therapeutic target for microtubule-associated diseases.
Main Methods:
- Biochemical assays to assess FKBP25's interaction with microtubules.
- Cellular studies involving FKBP25 knockdown to analyze effects on mitosis and chromosome stability.
- Phosphorylation site mapping to understand cell-cycle regulation of FKBP25.
Main Results:
- FKBP25 directly binds to microtubules, enhancing their polymerization and stabilizing the microtubule network.
- FKBP25 associates with the mitotic spindle, regulating mitotic entry and spindle dynamics.
- FKBP25 knockdown leads to increased chromosome instability, indicating its importance in faithful genome duplication.
- Protein Kinase C phosphorylation regulates FKBP25's association with chromatin during mitosis.
Conclusions:
- FKBP25 plays a critical role in microtubule dynamics and mitotic progression.
- The cell-cycle-dependent regulation of FKBP25 ensures proper genome duplication.
- FKBP25 is identified as a microtubule-associated FK506 receptor with therapeutic implications for microtubule-related disorders.
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