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Katanin and the Severing of Microtubules Journal of Cell Science 113, 2821-2827 (2000) 2821 Printed in Great Britain © The Company of Biologists Limited 2000 JCS0718 COMMENTARY Cellular Samurai: katanin and the severing of microtubules Lynne Quarmby Department of Biological Sciences, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6 ([email protected]) Published on WWW 20 July 2000 SUMMARY Recent biochemical studies of the AAA ATPase, katanin, difficult to establish the role of katanin in mitosis, new provide a foundation for understanding how microtubules genetic evidence indicates that a katanin-like protein, MEI- might be severed along their length. These in vitro studies 1, plays an essential role in meiosis in C. elegans. Finally, are complemented by a series of recent reports of direct in new proteins involved in the severing of axonemal vivo observation of microtubule breakage, which indicate microtubules have been discovered in the deflagellation that the in vitro phenomenon of catalysed microtubule system of Chlamydomonas. severing is likely to be physiological. There is also new evidence that microtubule severing by katanin is important for the production of non-centrosomal microtubules in cells Key words: Microtubule severing, Katanin, mei-1, C. elegans, such as neurons and epithelial cells. Although it has been Chlamydomonas INTRODUCTION around the circumference of the tubule each to be dissociated from tightly bound neighbours above, below and on two sides. Microtubules are highly dynamic structures, and their dynamic It seems likely that a modest disruption of the lattice would be behaviour is essential for fundamental processes such as cell propagated spontaneously, given the large amount of energy division and differentiation (for recent reviews, see Anderson, stored in the microtubule polymer. Structural studies have 1999; Cassimeris, 1999; Walczak, 2000). Much of the dynamic revealed that the protofilaments change from a ‘straight’ nature of microtubules is attributed to regulated growth and conformation to a ‘curved’ conformation upon hydrolysis of shrinkage of the polymer plus ends (dynamic instability) or to GTP by β-tubulin (Hyman et al., 1995). If the αβ-tubulin dimer the addition of subunits at the plus end while they are is part of a microtubule lattice when the GTP is hydrolysed, simultaneously lost from the minus end (treadmilling). But then the lattice restricts the conformational change, and the there exists an additional pathway by which microtubule tubulin is held in the ‘straight’ conformation (Downing and dynamics can be affected: microtubules can be broken or Nogales, 1998). Thus, perhaps the problem of severing a severed along their length. Whether microtubule severing is a microtubule reduces to one of disrupting a section of the lattice physiological pathway, used by cells to mediate changes in while restricting (or not) total disassembly along the length of their microtubule array, is a topic of increasing interest to the the tubule. Recent biochemical studies of the microtubule- cell biology community. severing ATPase katanin suggest a mechanism by which the requisite disruption could be generated. Katanin is a heterodimer consisting of a 60-kDa HOW ARE MICROTUBULES SEVERED? microtubule-stimulated ATPase that requires ATP hydrolysis to disassemble microtubules, and an 80-kDa subunit that targets It is relatively easy to understand how a linear actin polymer the complex to centrosomes and regulates the microtubule- can be severed along its length by the catalysed dissociation of severing activity of the p60 subunit (McNally and Vale, 1993; two adjacent actin subunits. In contrast, the problem of Hartman et al., 1998; McNally et al., 2000). On the basis of severing a microtubule is much more difficult to get one’s mind the presence of a conserved 230-residue module, katanin p60 around. Microtubules are made of α- and β-tubulin dimers has been shown to be a member of the AAA family of ATPases arranged head-to-tail into protofilaments that assemble, (ATPases Associated with various cellular Activities; McNally probably through the formation of a sheet, to form hollow tubes and Vale, 1993). Sequence analysis indicates that this is an that most commonly comprise 13 protofilaments (Downing and ancient class of proteins, which today are found in all five Nogales, 1998). Therefore, severing of a microtubule at a kingdoms and have a wide range of functions, including specific spot along its length requires thirteen or so subunits proteolysis, DNA replication, recombination, restriction and 2822 L. Quarmby transcription, sporulation, chelation, vesicle fusion, and dynein motor (a) activity (Neuwald et al., 1999). Many AAA proteins play roles in the assembly, operation, or disassembly of protein complexes. Orthologs of katanin p60 are present in humans, Chlamydomonas, Drosophila, C. elegans, and Arabidopsis, but not yeast. On the basis of data from rotary shadowing electron microscopy, and by analogy to other AAA proteins, Hartman et al. (1998) hypothesised that (b) p60 katanin functions as an oligomeric ring complex. However, in solution studies, katanin behaves as a dimer (McNally and Vale, 1993; Hartman and Vale, 1999). Hartman and Vale (1999) recently resolved this paradox, using mixtures of CFP-p60 and YFP-p60 fusion proteins, in which CFP and YFP function as donor-acceptor pairs for fluorescence resonance energy transfer (FRET) when the p60 subunits are neighbours in an oligomer (see McNally, 2000). In order to capture the Spindle pole Centrosome p60 katanin as an oligomer, the authors Treadmilling used an active-site mutant of p60 katanin (E334Q) designed to block the protein in its ATP-bound state. The Fig. 1. Microtubule severing by katanin. Katanin p60 subunits (swords) are shown as a ATPase activity of wild-type katanin is hexameric complex inserted into the face of a microtubule. Tubulin dimers are blue-green; maximal at a microtubule concentration red sword handles represent ATP; blue sword handles represent ADP; protective MAPs of 2-10 µM tubulin dimer; at higher (microtubule-associated proteins) are shown in purple. The samurai swordsmen represent concentrations of microtubules the accessory/regulatory proteins, possibly including katanin p80. (a) Accessory proteins are ATPase activity decreases (Hartman et absent in the in vitro assay (top panels), in which ATP binding triggers oligomerization, and al., 1998). Hartman and Vale (1999) assembly on the wall of the microtubule, which in turn triggers ATP hydrolysis and observed the same microtubule- phosphate release, which results in conformational changes in the katanin (the swords twist); concentration dependence for katanin the p60 subunits then dissociate, and directly affected tubulin dimers are wrenched from the microtubule lattice; disassembly of the lattice propagates around the circumference of the ATPase, microtubule severing and tubule (based, in part, on the data of Hartman and Vale, 1999). (b) Three of several possible oligomerization (as measured by in vivo contexts for microtubule severing. In cells, microtubule severing is likely to be FRET). controlled by regulatory factors, some of which might hold the severing complex together Taken together, the accumulated data after ATP hydrolysis (e.g. the samurai at the spindle pole), whereas others, such as protective on katanin and related AAA ATPases MAPs, might prevent the immediate disassembly of the new plus and minus ends. At the suggest the following model for spindle pole, severing might produce free microtubule ends, allowing for the poleward flux microtubule severing by katanin (see of tubulin and poleward movement of the microtubule. At the centrosome, microtubule Hartman and Vale, 1999). Microtubules severing might release microtubules. And in the cytoplasm, microtubule severing might act as a scaffold upon which katanin facilitate treadmilling. Other in vivo contexts for microtubule severing are discussed in the oligomerizes after it has exchanged its text. ADP for ATP. Once a complete katanin ring is assembled on the microtubule, the ATPase activity of could be reversibly masked by regulatory factors; and other katanin is stimulated. As a consequence of ATP hydrolysis factors could stimulate or inhibit ATP hydrolysis and severing. and subsequent phosphate release, the katanin undergoes a Different types of regulation might be used in different cellular conformational change leading to destabilisation of tubulin- contexts (see below), but the ubiquitous p80 subunit might well tubulin contacts. The ADP-bound katanin has lower affinity play a fundamental role. both for other katanin molecules and for tubulin; this leads to The in vivo function of the p80 subunit remains enigmatic, the dissolution of the complex and the recycling of the katanin but it is likely to play roles both in targeting and in regulation (see Fig. 1). of the p60 subunit. The N-terminal WD40 domain of p80 can This model suggests several possible points of regulation: a target a p80WD40-GFP chimera to interphase centrosomes nucleotide-exchange factor could regulate loading of p60 and is thus implicated in the targeting p60 to centrosomes with ATP; accessibility to microtubules could be regulated by (Hartman et al., 1998). Recent work from McNally et al. (2000) removal of protective MAPs; oligomerization sites on p60 demonstrates that both p60 and the C-terminal domain of p80 Cellular Samurai: katanin and the severing of microtubules 2823 bind to microtubules in vitro and that the association of the two end factor is
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