Kinesin-4 KIF21B is a potent microtubule pausing factor

Abstract

Microtubules are dynamic polymers that in cells can grow, shrink or pause, but the factors that promote pausing are poorly understood. Here, we show that the mammalian kinesin-4 KIF21B is a processive motor that can accumulate at microtubule plus ends and induce pausing. A few KIF21B molecules are sufficient to induce strong growth inhibition of a microtubule plus end in vitro. This property depends on non-motor microtubule-binding domains located in the stalk region and the C-terminal WD40 domain. The WD40-containing KIF21B tail displays preference for a GTP-type over a GDP-type microtubule lattice and contributes to the interaction of KIF21B with microtubule plus ends. KIF21B also contains a motor-inhibiting domain that does not fully block the interaction of the protein with microtubules, but rather enhances its pause-inducing activity by preventing KIF21B detachment from microtubule tips. Thus, KIF21B combines microtubule-binding and regulatory activities that together constitute an autonomous microtubule pausing factor.DOI: http://dx.doi.org/10.7554/eLife.24746.001

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

“…Proteomic studies identified 3 kinesins expressed during male gametogenesis (kinesin-8B, -13 and -15)(Khan et al, 2005;Talman et al, 2014), but no functional studies have been conducted until now. In other eukaryotes, orthologues for kinesin-4, -5, -8B, -13 and -15 are known to be involved in microtubule dynamics and particularly mitosis and cilia/flagella length regulation(Almeida & Maiato, 2018;Hu et al, 2015;Ma, Wang, & Yang, 2017;Muhia et al, 2016;Niwa, 2015;Niwa et al, 2012;Shrestha, Hazelbaker, Yount, & Walczak, 2018;Singh, Pandey, Al-Bassam, & Gheber, 2018;van Riel et al, 2017). Unfortunately, concerning PBANKA_0622400, PBANKA_0609500, PBANKA_0809500, PBANKA_0902400 and PBANKA_1224100, no functional data are available and the number of species possessing orthologues of these proteins is currently very limited, making it difficult to construct any hypothesis concerning their roles.…”

Microtubule binding of the kinesin-4 KIF7 and its regulation by autoinhibition

“…Mutations in this regulatory coiled-coil relieve autoinhibition and lead to the disease congenital fibrosis of the extraocular muscles type 1 (CFEOM1) [48–50]. An analogous regulatory coiled-coil segment plays a role in autoinhibition of KIF21B [51]. As noted by Bianchi et al [49], the regulatory coiled-coil segment of KIF21A shares 37.5% sequence similarity to amino acids 998-1077 of KIF7, suggesting that the mechanism of autoinhibition for KIF7 may involve interactions between this coiled-coil region and the motor domain.…”

“…In contrast, KIF7 and KIF27 decrease the microtubule growth rate and growth length, thus destabilizing microtubules [33, 37]. The influence of KIF21B on microtubule dynamics is unclear as one study suggested that KIF21B increases microtubule growth rates and another suggested that it decreases growth rates [51, 54].…”

“…For KIF21A, its loss of function resulted in an increase in microtubule growth rates whereas overexpression of KIF21A results in decreased microtubule growth [48, 50], also consistent with the in vitro results. The physiological relevance of KIF21B’s ability to influence microtubule dynamics are unclear as two studies suggested that KIF21B decreases growth rates and a third study demonstrated an increase in growth rates in cells [51, 54, 59]. For KIF7, loss of KIF7 expression or point mutations in Kif7 lead to increased cilium length [23, 33–35], consistent with KIF7 functioning to destabilize microtubules.…”

“…These results suggest that overexpression of active kinesin motors, above physiological levels, can influence microtubule dynamics in cells. This influence is likely to be indirect as neither KIF5C, KIF7 nor KIF21B regulated microtubule dynamics via localization to the plus ends (this study, [51]). One possibility is that the overexpressed motor domains may bind to soluble tubulin and remove subunits from the polymerization-competent pool.…”