Exploring intermediates in mechanochemical cycle and mechanism of regulation of full-length Dynein
Year: 2026
Type: preprint
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.
Source: ChemRxiv
Authors: Pradipta Kumar Das, Biman Jana
Institution: Indian Association for the Cultivation of Science
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7220845821