AI Article Synopsis
- Cytoplasmic dynein is a key motor protein that moves toward the microtubule minus end, requiring assembly with dynactin and a cargo adaptor for activation.
- Recent research suggests that Lis1 helps activate dynein by overcoming its autoinhibited state, while the role of Nde1/Ndel1 is less clear.
- This study found that Nde1 enhances dynein complex assembly by competing with PAF-AH for Lis1 binding and promoting the formation of active dynein-dynactin complexes, but excess Nde1 can inhibit dynein by competing for dynactin.
Article Abstract
Cytoplasmic dynein is the primary motor that drives the motility and force generation functions towards the microtubule minus end. The activation of dynein motility requires its assembly with dynactin and a cargo adaptor. This process is facilitated by two dynein-associated factors, Lis1 and Nde1/Ndel1. Recent studies proposed that Lis1 rescues dynein from its autoinhibited conformation, but the physiological function of Nde1/Ndel1 remains elusive. Here, we investigated how human Nde1 and Lis1 regulate the assembly and subsequent motility of the mammalian dynein/dynactin complex using in vitro reconstitution and single molecule imaging. We found that Nde1 promotes the assembly of active dynein complexes in two distinct ways. Nde1 competes with the α2 subunit of platelet activator factor acetylhydrolase (PAF-AH) 1B, which recruits Lis1 as a noncatalytic subunit and prevents its binding to dynein. Second, Nde1 recruits Lis1 to autoinhibited dynein and promotes Lis1-mediated assembly of dynein-dynactin-adaptor complexes. However, excess Nde1 inhibits dynein, presumably by competing against dynactin to bind the dynein intermediate chain. The association of dynactin with dynein triggers Nde1 dissociation before the initiation of dynein motility. Our results provide a mechanistic explanation for how Nde1 and Lis1 synergistically activate the dynein transport machinery.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10246013 | PMC |
| http://dx.doi.org/10.1101/2023.05.26.542537 | DOI Listing |
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