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Single-Molecule FRET Imaging for Observing the Conformational Dynamics of Dynamin-Like GTPase Atlastin
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Single-Molecule Structures and Kinetics of the AAA-ATPase Bcs1 Translocating Folded ISP
Yangang Pan1, Jingyu Zhan2, Zhaokun Wang1
1Department of Anesthesiology, Weill Cornell Medical College, 1300 York Ave, New York, NY 10065, USA.
Journal of Molecular Biology
|November 3, 2025
Summary
Bcs1, a unique AAA-ATPase, transports folded proteins across mitochondrial membranes using a fully coupled, concerted mechanism. This study reveals its distinct conformational coupling and substrate binding, uncovering a novel AAA-ATPase mechanism.
Area of Science:
- Mitochondrial biology
- Protein transport
- Biochemistry
Background:
- Bcs1 is a AAA-ATPase essential for transporting the Rieske iron-sulfur protein (ISP) across the inner mitochondrial membrane.
- Unlike typical AAA-ATPases, Bcs1 is a heptameric transmembrane protein that transports folded ISP via a concerted mechanism.
Purpose of the Study:
- To elucidate the mechanism of Bcs1-mediated transport of folded ISP.
- To investigate the conformational coupling and substrate binding dynamics of Bcs1.
Main Methods:
- Single-molecule analysis using high-speed atomic force microscopy (HS-AFM).
- Kinetic studies involving nucleotide analogs (AMP-PNP, ADP, ATP).
Main Results:
- Bcs1 subunits exhibit complete conformational coupling; the ring exists in either the AMP-PNP or ADP state, not a mixed conformation.
- Substrate ISP binds to the apo-conformation of Bcs1's AAA-domains within the matrix cavity.
- ISP binding is sufficiently long-lasting to ensure efficient transport during ATP turnover.
Conclusions:
- Bcs1 operates via a unique, concerted mechanism distinct from other AAA-ATPases.
- Conformational coupling and specific substrate binding are critical for Bcs1 function.
- This research reveals a novel AAA-ATPase mechanism essential for mitochondrial protein homeostasis.
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