New insights into the mechanism of dynein motor regulation by lissencephaly-1

Abstract

Lissencephaly (‘smooth brain’) is a severe brain disease associated with numerous symptoms, including cognitive impairment, and shortened lifespan. The main causative gene of this disease – lissencephaly-1 (LIS1) – has been a focus of intense scrutiny since its first identification almost 30 years ago. LIS1 is a critical regulator of the microtubule motor cytoplasmic dynein, which transports numerous cargoes throughout the cell, and is a key effector of nuclear and neuronal transport during brain development. Here, we review the role of LIS1 in cellular dynein function and discuss recent key findings that have revealed a new mechanism by which this molecule influences dynein-mediated transport. In addition to reconciling prior observations with this new model for LIS1 function, we also discuss phylogenetic data that suggest that LIS1 may have coevolved with an autoinhibitory mode of cytoplasmic dynein regulation.

Dynein activation in vivo is regulated by the nucleotide states of its AAA3 domain

“…The function of the cargo adapter has been implicated in enhancing the dyneindynactin interaction (Splinter et al, 2012;McKenney et al, 2014;Schlager et al, 2014;Olenick et al, 2016). In fungi, however, the dynein-dynactin interaction clearly occurs before cargo-adaptermediated dynein activation (Markus et al, 2020;Xiang & Qiu, 2020), especially since dynactin is absolutely required for dynein's plus-end accumulation in filamentous fungi (J. Zhang et al, 2003;Lenz et al, 2006;J.…”

“…Function of the cargo adapter has been implicated in enhancing the interaction between purified mammalian dynein and dynactin (Splinter et al, 2012;McKenney et al, 2014;Schlager et al, 2014;Olenick et al, 2016). However, since dynein and dynactin interact before cargo binding in some in vivo systems (Markus et al, 2020;Xiang & Qiu, 2020), additional regulatory mechanisms may exist to ensure that dynein is not activated by dynactin alone before cargo binding.…”

“…However, this interesting idea has not yet been examined in vivo in the context of cargo adapter, dynactin and another important dynein regulator LIS1. LIS1 is a causal gene for human lissencephaly and a known dynein regulator in many organisms and cell types (Reiner et al, 1993;Wynshaw-Boris, 2007;Markus et al, 2020), and it binds to the dynein motor ring around AAA3/AAA4 and to a site on the stalk (Huang et al, 2012;Toropova et al, 2014;DeSantis et al, 2017;Htet et al, 2020). Different AAA3 nucleotide states cause the yeast dynein motor domain to respond to LIS1 differently in vitro: While LIS1 strongly inhibits the motility of apo-AAA3 dynein, it enhances the motility of ATP-AAA3 dynein (DeSantis et al, 2017).…”

Structural Basis for Cytoplasmic Dynein-1 Regulation by Lis1

“…In addition to dynactin and an activating adaptor, dynein function in vivo also requires Lis1. Genetically, Lis1 is a positive regulator of dynein function (Geiser et al, 1997;Liu et al, 1999;Xiang et al, 1995) and is required for most, if not all, dynein functions in many organisms (Markus et al, 2020). In humans, mutations in both Lis1 (PAFAH1B1) and the dynein heavy chain (DYNC1H1) cause the neurodevelopmental disease lissencephaly (Parrini et al, 2016;Reiner et al, 1993).…”

Cytoskeletal regulation guides neuronal trafficking to effectively supply the synapse

“…Additional non-catalytic subunits include two intermediate chains, two light intermediate chains, and additional light chains 28 . Dynein is tightly regulated by the binding of additional co-factors, including the multisubunit dynactin complex and LIS1, and cargo-specific activating adaptors, such as the BICD, HOOK, and HAP/TRAK families of proteins 81,82 . The stable tripartite dynein-dynactin-activating adaptor complex drives processive motility toward the microtubule minus end at velocities of 1 mm/sec.…”