Pac1/LIS1 stabilizes an uninhibited conformation of dynein to coordinate its localization and activity

Cargo-Mediated Activation of Cytoplasmic Dynein in vivo

“…Importantly, a phi mutation that promotes open dynein (Zhang K. et al, 2017) bypasses the requirement for LIS1 to a significant extent (Qiu et al, 2019), suggesting that LIS1 is involved in promoting open dynein, thereby facilitating cargo adapter-mediated dynein activation (Qiu et al, 2019). This main conclusion agrees with three other recent studies (Elshenawy et al, 2020;Htet et al, 2020;Marzo et al, 2020), although LIS1 in A. nidulans does not seem to significantly affect the formation of the dynein-dynactin-C-Hook complex (Qiu et al, 2019), while LIS1 enhances the recruitment of the second dynein to the dynein-dynactin-BicD2N complexes in vitro (Elshenawy et al, 2020;Htet et al, 2020). Possibly, A. nidulans LIS1 still enhances the dynein-dynactin interaction as described in other systems (Dix et al, 2013;Wang et al, 2013), but this effect was not easily detected when the concentration of cytosolic cargo adapters is high enough.…”

“…In contrast to dynactin that binds to the dynein tail (Karki and Holzbaur, 1995;Vaughan and Vallee, 1995;Chowdhury et al, 2015;Urnavicius et al, 2015), LIS1 binds directly to the dynein motor ring at AAA3/AAA4 as shown by cryo-EM studies (Huang et al, 2012;Toropova et al, 2014;Desantis et al, 2017;Htet et al, 2020). LIS1's binding to this site is not compatible with the autoinhibited phi conformation of dynein (Htet et al, 2020;Marzo et al, 2020), which supports a "check valve" (Markus et al, 2020) model of LIS1 mechanism of action: it stabilizes the open dynein conformation and prevents it from switching to the autoinhibited phi state, thereby facilitating cargo-adapter-mediated dynein activation (Qiu et al, 2019;Canty and Yildiz, 2020;Elshenawy et al, 2020;Htet et al, 2020;Markus et al, 2020;Marzo et al, 2020).…”

“…Beside dynactin and cargo adapters, another important protein involved in dynein activation is LIS1 (Lissencephaly-1) (Markus et al, 2020). The mechanism of LIS1 action in the dynein pathway has been controversial, but multiple recent studies suggest that LIS1 promotes the open dynein conformation, thereby facilitating dynein activation (Qiu et al, 2019;Elshenawy et al, 2020;Htet et al, 2020;Marzo et al, 2020;McKenney, 2020). LIS1, a WD40-repeats-containing protein, was initially identified as a causal gene for type 1 lissencephaly, a human brain developmental disorder (Reiner et al, 1993).…”

“…Possibly, A. nidulans LIS1 still enhances the dynein-dynactin interaction as described in other systems (Dix et al, 2013;Wang et al, 2013), but this effect was not easily detected when the concentration of cytosolic cargo adapters is high enough. We should also point out that LIS1 may play roles beyond stabilizing the open dynein because constitutively opening dynein does not allow the requirement for LIS1 to be completely bypassed (Qiu et al, 2019;Elshenawy et al, 2020;Htet et al, 2020;Marzo et al, 2020).…”

Tubulin mutations in neurodevelopmental disorders as a tool to decipher microtubule function

“…However, Lis1 is best known as a key dynein motor regulator and is required for the efficient transport of many dynein‐associated cargoes within cells [105,110–112]. In vitro studies using purified recombinant protein, and more recently single‐molecule imaging and motility assays, have established that Lis1 promotes dynein activity and orchestrates dynein–dynactin transport machinery assembly [72,73,113–115]. Lis1 also interacts with the MT plus‐end‐binding protein CLIP‐170 (see below) [116,117] and with the dynein regulator Nde1 [109,118–121].…”