Structural insights into Fe-S protein biogenesis by the CIA targeting complex
Susanne A Kassube1, Nicolas H Thomä2
1Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Nature Structural & Molecular Biology
|July 8, 2020
Summary
The cytosolic iron-sulfur (Fe-S) assembly (CIA) pathway
Area of Science:
- Molecular biology
- Biochemistry
- Structural biology
Background:
- The cytosolic iron-sulfur (Fe-S) assembly (CIA) pathway is crucial for cellular function, supplying Fe-S clusters to essential proteins.
- Understanding how the CIA pathway targets and delivers Fe-S clusters to client proteins is vital for comprehending DNA replication and repair.
- The precise mechanisms of client protein recognition and Fe-S cluster transfer within the CIA pathway are not fully elucidated.
Purpose of the Study:
- To elucidate the structural basis of client protein recognition and Fe-S cluster transfer by the CIA targeting complex (CTC).
- To investigate the role of CTC subunits, particularly CIAO1, CIAO2B, and MMS19, in mediating Fe-S cluster delivery.
- To uncover the mechanism of Fe-S cluster transfer to specific DNA replication and repair factors.
Main Methods:
- X-ray crystallography to determine the structure of the CTC.
- Cryo-electron microscopy (Cryo-EM) to visualize CTC complexes bound to client proteins.
- Biochemical and biophysical assays to analyze protein interactions and Fe-S cluster transfer.
- Yeast complementation assays to assess functional relevance in vivo.
Main Results:
- Crystal structures revealed the central role of CIAO2B in bridging CIAO1 and MMS19 within the CTC.
- Cryo-EM and biochemical data demonstrated an evolutionarily conserved, bipartite client recognition mechanism involving CIAO1 and flexible MMS19.
- Fe-S cluster in the primase client protein was found distant from the CTC reactive cysteine, suggesting dynamic transfer mechanisms or involvement of other factors.
Conclusions:
- The CTC utilizes a bipartite recognition mode involving CIAO1 and MMS19 for targeting client proteins.
- Structural flexibility of MMS19 plays a key role in client interaction and Fe-S cluster delivery.
- The unexpected positioning of the Fe-S cluster suggests complex conformational dynamics or additional factors are involved in the final transfer step.
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