Exploring intermediates in mechanochemical cycle and mechanism of regulation of full-length Dynein
- 1School of Chemical Sciences
- 2Indian Association for the Cultivation of Science
Abstract
Cytoplasmic dynein is a complex hexameric AAA+ motor protein essential for intracellular transport, yet the structural mechanisms and domain cooperativity driving its mechanochemical cycle remain incompletely understood. In this study, we utilize a dual-basin structure-based model (SBM) to simulate the full-length dynein cycle in the presence of microtubules. Rather than a single concerted transition, our results reveal that dynein moves through discrete, on-pathway conformational intermediates, including a transient, ADP-bound state that bridges the pre- and post-powerstroke configurations. We identify four key regulatory interfaces (AAA1-subdomains, AAA1–AAA2, AAA3–AAA4, and AAA5–AAA6) that function as checkpoints to couple the AAA+ ring changes to power- and recovery stroke. Crucially, we elucidate the regulatory roles of the non-dominant domains: suppressing AAA3 disrupts recovery-stroke progression and linker relocation, while suppressing AAA4 selectively impairs linker stabilization and docking. Together, these findings demonstrate that dynein's force generation relies on a highly coordinated allosteric network across the entire AAA+ ring.
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BibTeX
@misc{das2026exploring,
title = {{Exploring intermediates in mechanochemical cycle and mechanism of regulation of full-length Dynein}},
author = {Pradipta Kumar Das and Biman Jana},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010025/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010025/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Exploring intermediates in mechanochemical cycle and mechanism of regulation of full-length Dynein
AU - Pradipta Kumar Das
AU - Biman Jana
PY - 2026
DA - 2026/10/07
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010025/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010025/v1
AB - Cytoplasmic dynein is a complex hexameric AAA+ motor protein essential for intracellular transport, yet the structural mechanisms and domain cooperativity driving its mechanochemical cycle remain incompletely understood. In this study, we utilize a dual-basin structure-based model (SBM) to simulate the full-length dynein cycle in the presence of microtubules. Rather than a single concerted transition, our results reveal that dynein moves through discrete, on-pathway conformational intermediates, including a transient, ADP-bound state that bridges the pre- and post-powerstroke configurations. We identify four key regulatory interfaces (AAA1-subdomains, AAA1–AAA2, AAA3–AAA4, and AAA5–AAA6) that function as checkpoints to couple the AAA+ ring changes to power- and recovery stroke. Crucially, we elucidate the regulatory roles of the non-dominant domains: suppressing AAA3 disrupts recovery-stroke progression and linker relocation, while suppressing AAA4 selectively impairs linker stabilization and docking. Together, these findings demonstrate that dynein's force generation relies on a highly coordinated allosteric network across the entire AAA+ ring.
ER -