Figure 3. The ‘catalytic check valve’ model for LIS1 function.
The new model for LIS1 function posits the following mode of action: dynein stochastically switches from closed (phi conformation, red), to open states (green; accessory chains shown in gray for both states) (Marzo et al., 2020). Adopting the latter state is likely a rate-limiting step in assembly of dynein-dynein-adaptor (DDA) complexes (Zhang et al., 2017). LIS1/Pac1 preferentially binds dynein in the open state (Htet et al., 2020; Marzo et al., 2020), and acts as a ‘check valve’ that prevents the return of dynein to the phi conformation (Box 1). In so doing, LIS1/Pac1 promotes assembly of active, processive DDA (with only one dimer, dimer A) and D2DA complexes (with dimers A and B). The probability of D2DA forming may be the product of the probability of a DDA complex assembling times itself (pDDA x pDDA); however, it is possible that the addition of the 2nd dynein dimer (dimer B) occurs cooperatively due to the number of apparent contacts between the two dynactin-bound dynein dimers (Urnavicius et al., 2018), in which case the probability of D2DA assembly is greater than pDDA2. In either case, by increasing the probability of DDA complex assembly, addition of LIS1 also increases the probability of D2DA assembly, as has been observed in vitro (Elshenawy et al., 2020; Htet et al., 2020). In addition to stabilizing the open conformation, LIS1 also promote DDA/D2DA complex by an unknown mechanism that may involve LIS1-mediated dynein allostery, or linking dimer B to dimer A (Box 2; see text). It is interesting to note that LIS1 does not need to comigrate with dynein to affect DDA (or D2DA) motility; in fact, studies show that LIS1/Pac1 does not localize with dynein cargoes in cells, and may dissociate in a regulated manner prior to initiation of cargo transport (Jha et al., 2017; Lammers and Markus, 2015). In this way, LIS1 acts catalytically to increase DDA and D2DA assembly.