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Microtubules are highly dynamic polymeric filaments that are required for a diverse array of essential cellular processes, such as cell division, motility and determination of cell shape. Microtubules participate in these functions by serving as scaffolds for organelle positioning and intracellular transport, and by exerting pulling and pushing forces on different subcellular structures. Microtubules assemble from dimers of α- and β-tubulin that align head-to-tail to form protofilaments, which associate laterally into tubes. This particular arrangement, together with the property that the αβ-tubulin heterodimer is asymmetric, leads to the intrinsically polarized microtubule structure comprising two distinct ends (see poster). The end where α-tubulin is exposed (termed the minus end) grows slowly in vitro, whereas the opposite end where β-tubulin faces into solution (termed the plus end) grows rapidly (Desai and Mitchison, 1997; Nogales and Wang, 2006). Both microtubule ends can switch between phases of growth and shrinkage, a process that depends on GTP hydrolysis on β-tubulin (Desai, and Mitchison, 1997). In cells, microtubule plus ends are responsible for the formation of the microtubule mass and for dynamic interactions with different subcellular structures. In contrast, the minus ends determine the geometry of microtubule networks because they are often stably anchored at sites where microtubules are nucleated (Akhmanova and Steinmetz, 2015; Martin and Akhmanova, 2018). A number of specific microtubule minus-end regulators have been identified. It is becoming increasingly clear that they represent a structurally and functionally diverse group of factors that control microtubule organization and, thus, play a crucial role in defining cell architecture. In this review and the accompanying poster, we provide an overview of the current knowledge on the structure, interactions and functions of cellular factors that specifically interact with microtubule minus ends, and that regulate their dynamics and organization.
Tubulin addition in cells occurs mainly at microtubule plus ends, whereas microtubule minus ends often remain associated with their original nucleation sites. One reason for this behavior is that the key microtubule nucleator, the γ-tubulin ring complex (γ-TuRC), caps microtubule minus ends by binding to their exposed α-tubulin subunits (reviewed by Kollman et al., 2011; see poster).
γ-TuRC blocks the exchange of tubulin dimers at minus ends (Wiese and Zheng, 2000); however, not all microtubule minus ends in cells are capped. For example, spindle microtubules slowly disassemble at the minus ends and elongate at the plus ends, a process that leads to the poleward flux of microtubule polymers (Borgal and Wakefield, 2018; Rogers et al., 2005). In interphase, the disassembly of free microtubule minus ends contributes to the turnover of radial centrosomal microtubule arrays (Rodionov et al., 1999).
Completely different minus-end regulators in vertebrates are components of an interphase chromatin-associated protein complex termed KANSL that contains the KAT8 regulatory NSL complex subunits 1 and 3 (KANSL1 and KANSL3), which can recognize the minus ends of stabilized microtubules (Meunier et al., 2015). The KANSL complex contains another factor, the microspherule protein 1 (MCRS1), which shows no minus-end preference on its own but participates in spindle formation by promoting minus-end stability of kinetochore fibers (Meunier et al., 2015; Meunier and Vernos, 2011). The activity of the KANSL complex on dynamic minus ends in vitro has not yet been described.
In addition to the specific minus-end regulators discussed above, a number of proteins show association with both microtubule ends. End-binding (EB; MAPRE) proteins, for example, are classified as microtubule plus-end tracking proteins (+TIPs) based on their localization behavior in cells; however, in vitro, EBs autonomously track growing microtubule plus- and minus ends, because they show strong preference for the GTP or GDP-Pi cap (Bieling et al., 2007; Maurer et al., 2012; Zhang et al., 2015). The size of this cap decreases at low microtubule growth rates, and thus under physiological conditions, the actual minus-end accumulation of the EBs, as well as that of the numerous partners they can recruit to microtubule tips, is low (Akhmanova and Steinmetz, 2015).
Other proteins, such as members of the microtubule depolymerase kinesin-13 family or the microtubule-severing enzyme katanin, can show preference to microtubule ends possibly because of the increased protofilament curvature present at this location (Asenjo et al., 2013; Jiang et al., 2017). These proteins can either compete or cooperate with specific microtubule minus-end regulators (see poster). For example, the microtubule depolymerase activity of the members of the kinesin-13 family, such as the mitotic centromere-associated kinesin (MCAK; officially known as KIF2C), is counteracted by CAMSAP/Patronin as well as by the KANSL complex (Atherton et al., 2017; Goodwin and Vale, 2010; Meunier and Vernos, 2011). Katanin, on the other hand, can specifically bind to CAMSAPs and ASPM and cooperate with them by inhibiting microtubule minus-end growth (Jiang et al., 2014; Jiang et al., 2017).
Another important microtubule minus-end associated protein is the nuclear mitotic apparatus protein 1 (NUMA1, hereafter referred to as NuMA; known as mushroom body defect, Mud, in Drosophila), which acts in complex with cytoplasmic dynein and dynactin (Merdes et al., 1996). NuMA contains a microtubule-binding domain that associates with both microtubule plus- and minus ends in vitro (Seldin et al., 2016). In mitotic cells, NuMA can be recruited to freshly severed microtubule minus ends independently of dynein and other known mitotic minus-end regulators and plays a key role in focusing microtubule minus ends at spindle poles (Hueschen et al., 2017). The origin of the microtubule minus-end preference of NuMA is currently unclear.
In contrast to proteins that interact with both microtubule ends, our understanding of specific minus-end binders is much less advanced. These proteins are supposed to recognize structural features that are only present at minus ends and not at plus ends. One such prominent feature that is only exposed at minus ends is the surface of α-tubulin, which is involved in longitudinal tubulin-tubulin interactions along protofilaments. This surface is recognized by the γ-tubulin subunits of the γ-TuRC complex, which readily explains the specificity of the γ-TuRC towards minus ends (reviewed by Kollman et al., 2011; see poster).
Another compound that can affect microtubule minus-end regulation is gatastatin, which binds to γ-tubulin and inhibits microtubule nucleation (Chinen et al., 2015). This property of gatastatin can be exploited in order to dissect the relative importance of γ-TuRC-dependent and -independent nucleation pathways; however, the interpretation of results in cells might be complicated by the fact that this compound also has some affinity for αβ-tubulin (Chinen et al., 2015).
We thank Carolyn Moores and Joseph Atherton (Birkbeck University of London, UK), and Ruddi Rodriguez-Garcia, Shasha Hua and Kai Jiang (formerly A.A.'s laboratory, Utrecht University, The Netherlands) for preparing images shown on poster.
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