Motility and microtubule depolymerization mechanisms of the Kinesin-8 motor, KIF19A

Abstract

The kinesin-8 motor, KIF19A, accumulates at cilia tips and controls cilium length.Defective KIF19A leads to hydrocephalus and female infertility because of abnormally elongated cilia. Uniquely among kinesins, KIF19A possesses the dual functions of motility along ciliary microtubules and depolymerization of microtubules. To elucidate the molecular mechanisms of these functions we solved the crystal structure of its motor domain and determined its cryoelectron microscopy structure complexed with a microtubule. The features of KIF19A that enable its dual function are clustered on its microtubule-binding side. Unexpectedly, a destabilized switch II coordinates with a destabilized L8 to enable KIF19A to adjust to both straight and curved microtubule protofilaments. The basic clusters of L2 and L12 tether the microtubule. The long L2 with a characteristic acidic-hydrophobic-basic sequence effectively stabilizes the curved conformation of microtubule ends. Hence, KIF19A utilizes multiple strategies to accomplish the dual functions of motility and microtubule depolymerization by ATP hydrolysis.

Kinesin-8B controls basal body function and flagellum formation and is key to malaria parasite transmission

“…Kinesin motors participate in diverse functions in many processes including cell division, intracellular transport, intraflagellar transport and controlling MT dynamics ((Cross and McAinsh, 2014;Dawson et al, 2007;Scholey, 2008;Verhey and Hammond, 2009). The lack of association of kinesin-8B with mitotic assembly within the nucleus -and with kinetochores in particular -is distinct from what is seen for kinesin-8As in most eukaryotes (Savoian et al, 2004;Savoian and Glover, 2010;Wang et al, 2016). The metazoan kinesin-8B, Kif19, is involved in ciliary length regulation, but the role of kinesin-8B in axonemal assembly appears to be more profound in Plasmodium than controlling length alone.…”

A Tubulin Binding Switch Underlies Kip3/Kinesin-8 Depolymerase Activity

“…While this manuscript was in preparation, the structure and characterization of a ciliary kinesin-8, Kif19A, was reported (Wang et al, 2016). Broadly consistent with our conclusions, the switch II cluster of monomeric Kif19A was poorly ordered, leading to the inference of conformational flexibility in the microtubule binding surface that could enable Kif19A to bind both curved and straight tubulin.…”

Vital role forPlasmodium bergheiKinesin8B in axoneme assembly during male gamete formation and mosquito transmission

“…They can walk on microtubules, but also regulate microtubule length, during mitosis (Gergely, Crapo, Hough, McIntosh, & Betterton, 2016;Grissom et al, 2009;Gupta, Carvalho, Roof, & Pellman, 2006;McHugh, Gluszek, & Welburn, 2018;Savoian & Glover, 2010), and/or ciliary and flagellar assembly (Hu, Liang, Meng, Wang, & Pan, 2015;Niwa et al, 2012;Wang et al, 2016). They can walk on microtubules, but also regulate microtubule length, during mitosis (Gergely, Crapo, Hough, McIntosh, & Betterton, 2016;Grissom et al, 2009;Gupta, Carvalho, Roof, & Pellman, 2006;McHugh, Gluszek, & Welburn, 2018;Savoian & Glover, 2010), and/or ciliary and flagellar assembly (Hu, Liang, Meng, Wang, & Pan, 2015;Niwa et al, 2012;Wang et al, 2016).…”

“…While most kinesins display predominantly one activity, either transport along microtubules or depolymerization, kinesin-8 family members are reportedly multitalented. They can walk on microtubules, but also regulate microtubule length, during mitosis (Gergely, Crapo, Hough, McIntosh, & Betterton, 2016;Grissom et al, 2009;Gupta, Carvalho, Roof, & Pellman, 2006;McHugh, Gluszek, & Welburn, 2018;Savoian & Glover, 2010), and/or ciliary and flagellar assembly (Hu, Liang, Meng, Wang, & Pan, 2015;Niwa et al, 2012;Wang et al, 2016). In Plasmodium, PbKIN8B could therefore be involved in several steps of microgametogenesis, such as DNA replication, axoneme assembly and function, as well as male gamete exflagellation.…”