The kinesin-5 tail domain directly modulates the mechanochemical cycle of the motor domain for anti-parallel microtubule sliding

Abstract

Kinesin-5 motors organize mitotic spindles by sliding apart microtubules. They are homotetramers with dimeric motor and tail domains at both ends of a bipolar minifilament. Here, we describe a regulatory mechanism involving direct binding between tail and motor domains and its fundamental role in microtubule sliding. Kinesin-5 tails decrease microtubule-stimulated ATP-hydrolysis by specifically engaging motor domains in the nucleotide-free or ADP states. Cryo-EM reveals that tail binding stabilizes an open motor domain ATP-active site. Full-length motors undergo slow motility and cluster together along microtubules, while tail-deleted motors exhibit rapid motility without clustering. The tail is critical for motors to zipper together two microtubules by generating substantial sliding forces. The tail is essential for mitotic spindle localization, which becomes severely reduced in tail-deleted motors. Our studies suggest a revised microtubule-sliding model, in which kinesin-5 tails stabilize motor domains in the microtubule-bound state by slowing ATP-binding, resulting in high-force production at both homotetramer ends.

Plasmodium bergheikinesin-5 associates with the spindle apparatus during cell division and is important for efficient production of infectious sporozoites

“…contains an N-terminal kinesin motor domain, a central stalk and a C-terminal tail domain [1], and forms a bipolar homotetramer that cross-bridges and slides on parallel and antiparallel microtubules (MTs) [9]. The motor domain binds microtubules (MTs) and hydrolyses ATP, which are conserved functions, while the tail region can also bind MTs, regulates motor activity [10] and helps localization during mitosis [10,11]. The stalk contains a coiled-coil region and neck linker that promote oligomerization and direction of movement, respectively [12].…”

Plasmodium berghei Kinesin-5 Associates With the Spindle Apparatus During Cell Division and Is Important for Efficient Production of Infectious Sporozoites

“…Kinesin-5 contains an N-terminal kinesin motor domain, a central stalk and a C-terminal tail domain ( Wojcik et al., 2013 ), and forms a bipolar homotetramer that cross-bridges and slides on parallel and anti-parallel microtubules (MTs) ( Kapitein et al., 2008 ). The motor domain binds microtubules (MTs) and hydrolyzes ATP, which are conserved functions, while the tail region can also bind MTs, regulate motor activity ( Bodrug et al., 2020 ) and help localization during mitosis ( Weinger et al., 2011 ; Bodrug et al., 2020 ). The stalk contains a coiled-coil region and neck linker that promote oligomerization and direction of movement, respectively ( Hesse et al., 2013 ).…”

Kinesin family member 23 (KIF23) contributes to the progression of bladder cancer cells in vitro and in vivo

“…Except for KIF23, the effects of other kinesins have been widely revealed [25]. KIF11 could enhance the self-renewal capacity of breast cancer via Wnt pathway [26].…”