Abstract
ASPM (known as Asp in fly and ASPM-1 in worm) is a microcephaly-associated protein family that regulates spindle architecture, but the underlying mechanism is poorly understood. Here, we show that ASPM forms a complex with another protein linked to microcephaly, the microtubule-severing ATPase katanin. ASPM and katanin localize to spindle poles in a mutually dependent manner and regulate spindle flux. X-ray crystallography revealed that the heterodimer formed by the N- and C-terminal domains of the katanin subunits p60 and p80, respectively, binds conserved motifs in ASPM. Reconstitution experiments demonstrated that ASPM autonomously tracks growing microtubule minus ends and inhibits their growth, while katanin decorates and bends both ends of dynamic microtubules and potentiates the minus-end blocking activity of ASPM. ASPM also binds along microtubules, recruits katanin and promotes katanin-mediated severing of dynamic microtubules. We propose that the ASPM–katanin complex controls microtubule disassembly at spindle poles and that misregulation of this process can lead to microcephaly.
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Change history
22 May 2017
In the original version of this Article, the name of author A. F. Maarten Altelaar was coded wrongly, resulting in it being incorrect when exported to citation databases. This has now been corrected, though no visible changes will be apparent.
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Acknowledgements
We thank A. Prota for the help in refining the crystal structures, M. Boxem, C. Janke and M. Mikhaylova for the gift of materials, and the beamline scientists at beamlines X06DA of the Swiss Light Source (Paul Scherrer Institut, Villigen, Switzerland) for technical assistance with the X-ray data collection. This work was supported by the European Research Council Synergy grant 609822 and Netherlands Organization for Scientific Research (NWO) CW ECHO grant (711.011.005) to A.A., the EMBO long-term and Marie Curie IEF fellowships to L.R., grants from the Swiss National Science Foundation (31003A_166608 to M.O.S. and 31003A_163449 to R.A.K.), a NWO VIDI grant (723.012.102) to A.F.M.A. and as part of the National Roadmap Large-scale Research Facilities of the Netherlands (project number 184.032.201) to A.F.M.A. and A.J.R.H. The structural data reported in this paper are available in PDB (PDB code 5LB7).
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K.J., L.R., S.H., R.A.K., M.O.S. and A.A. designed experiments, analysed data and wrote the paper. A.A. coordinated the project. K.J. and S.H. performed cellular and in vitro reconstitution experiments. L.R. performed biophysical experiments. L.R. and G.C. performed crystallography experiments. Q.L., A.F.M.A. and A.J.R.H. performed and analysed mass spectrometry experiments.
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Integrated supplementary information
Supplementary Figure 1 Characterization of ASPM knock-in cell lines.
(a) Genotyping of GFP and strep-GFP-ASPM knock-in cells used in this study. (b) Immunostaining for α-tubulin and DNA (DAPI) in GFP-ASPM knock-in HeLa cells during mitosis. White arrows indicate the localization of ASPM to the microtubule minus ends in the central spindle in telophase. Scale bar, 5 μm.
Supplementary Figure 2 ASPM and katanin regulate spindle architecture.
(a) western blotting with the indicated antibodies in control, ASPM knockout and p80 knockout cells (left, HeLa; right, U2OS PA-GFP-α-tubulin). Note that the knockout of p80 caused the concomitant loss of p60, in agreement with the fact that the two subunits form a tight complex. (b) Sequencing results of ASPM knockout cell lines used in this study. 1 nt insertion will result in p.N71KfsX31 or p.E72RfsX30. (c–d) Immunostaining of γ-tubulin, DNA (DAPI), and NuMA (c) or p150Glued (d) in control, ASPM knockout, and p80 knockout HeLa cells. Scale bar, 5 μm. In HeLa cells, the intensity of NuMA and p150Glued at the spindle pole remained largely unchanged in both ASPM and p80 knockout cells. (e) Quantification of spindle pole intensities of NuMA, and p150Glued as shown in panels c, d. For NuMA intensity, n = 164 spindle poles, control; n = 172, ASPM knockout; n = 176, p80 knockout. For p150Glued intensity, n = 160, control; n = 166, ASPM knockout; n = 170, p80 knockout. (f,g) Immunostaining for α-tubulin, CEP135 and DNA in control, ASPM knockout and p80 knockout HeLa cells (f, bipolar spindles with two centrosomes; g, bipolar and multipolar spindles with >2 centrosomes in p80 knockout cells). Scale bar, 5 μm. (h) Quantification of the distance between two centrosomes in control, ASPM knockout and p80 knockout HeLa cells as shown in f. n = 67 cells, control; n = 61, ASPM knockout, n = 90, p80 knockout. (i) Quantification of centrosome numbers as shown in f,g. 470 cells, control; 469, ASPM knockout; 572, p80 knockout (2 experiments). (j) Quantification of the average distance between two spindle poles in photoactivation experiments in U2OS cells as shown in Fig. 2e. n = 26 cells, control; n = 29, ASPM knockout; n = 26, p80 knockout. The standard deviations of the distance between the two poles during imaging were small (∼0.3 μm), which means that the spindle length kept constant during imaging. Compared to control, spindle length in ASPM and p80 knockout HeLa (h) and U2OS (j) cells shows 6 ∼ 10% reduction. Data represent mean ± s.d.∗, P < 0.05, ∗∗∗, P < 0.001, Mann-Whitney U test. Unprocessed original scans of blots are shown in Supplementary Fig. 8. Source data for panels e,h,i and j can be found in Supplementary Table 5.
Supplementary Figure 3 The interaction between ASPM and katanin requires a conserved repeat sequence of ASPM and the p60N/p80C heterodimer.
(a) Alignment of katanin-binding linear motifs of ASPM from several vertebrate species. Note the complete conservation of the phenylalanine residue corresponding to F352 in the third repeat of mouse ASPM (red arrowhead below the alignment). (b) Streptavidin pull down assays with extracts of HEK293T cells expressing Biotinylation tagged (Bio)-GFP-tagged wild-type (WT) p80 or its indicated mutants together with GFP-tagged WT p60 or the indicated mutants. None of the analyzed mutations perturbed the p60–p80 interaction. See also Supplementary Fig. 8e. (c) Electron density maps of ASPMp in the p60N/p80C/ASPMp complex structure. Only residues S351, F352 and L353 of the ASPMp peptide (LSPDSFLND, residues 347–355 of mouse ASPM) are visible. The SigmaA-weighted 2mFo-DFc (left) and mFo-DFc (right) omit maps (green mash) are contoured at +1.0σ and +3.0σ, respectively.
Supplementary Figure 4 The CH1-CH3 fragment of C. elegans ASPM-1 binds microtubule minus-end in cells.
(a,b) The worm ASPM-1 CH1–CH3 fragment associates with minus ends of free microtubules (a) or minus ends freshly generated by photoablation (b) in interphase MRC5 cells. Green lightning bolts indicate the sites of photoablation. Scale bars, 2 μm.
Supplementary Figure 5 The katanin p60/p80 heterodimer decorates and bends microtubule ends.
(a) TIRFM live cell imaging and kymographs of colocalization of GFP-p60/p80C and EB3-TagRFP in MRC5 cells. Scale bars: horizontal, 2 μm; vertical, 10 s. (b) Live cell images of a single microtubule plus end bound to GFP-p60/p80C and EB3-TagRFP in MRC5 cells. White arrow, breaking of a bent microtubule end. Scale bar, 1 μm. (c) Live imaging of MRC5 cells expressing individual katanin subunits together with EB3-TagRFP. Scale bar, 2 μm. (d) TIRFM time lapse images showing the complete severing of dynamic microtubules by p60/SNAP-Alexa647-p80C at 750 nM in a flow-in experiment. Time represented as min:sec. Scale bar, 2 μm. (e–f) Maximum intensity projections of time lapse images of GFP-p60/p80 WT or mutants in HeLa cells. Imaging was performed using TIRFM with 500 ms exposure in a stream mode. 100–200 images representing consecutive frames were used to make projections. Mutations of R615A, K618A, G607A, V608A, D609A and I610A in p80 completely abolish the end-binding activity of p60/p80 in cells. Scale bar, 2 μm. (g) Protein sequence alignment of p60N and p80C from Caenorhabditis elegans, Chlamydomonas reinhardtii, Tetrahymena thermophila, Arabidopsis thaliana, Drosophila melanogaster , Danio rerio, Xenopus tropicalis, Homo sapiens and Mus musculus. The residues that are essential for microtubule end binding are indicated with red dots. Mutating charged residues denoted by black dots to alanine had no effect on end binding in vivo. Red triangles indicate the residues interacting with ASPM, which are conserved in vertebrates (red dashed rectangle). Numbers displayed on top of the sequence alignment are based on mouse katanin sequences.
Supplementary Figure 6 Characterization of wild-type katanin p60/p80C and its mutants, ASPM mutant and the ASPM–katanin complex at different concentrations.
(a) The p60/p80C R615A mutant does not bind microtubule ends at 25 or 75 nM. Time represented as min:sec. Scale bars, 2 μm. (b) The p60/p80C Y574A mutant can decorate, bend and break microtubule ends at 75 nM but not at 25 nM. White arrow, breaking of a bent microtubule end. Time represented as min:sec. Scale bars, 2 μm. (c) Wild-type (WT) p60/p80C and the indicated mutants can efficiently sever GMPCPP-stabilized microtubules at 75 nM but not at 25 nM. See Fig. 7a for quantification. Scale bar, 2 μm. (d–g) The p60/p80C R615A mutant but not the Y574A mutant at 25 nM can be recruited onto microtubule lattice and perform severing in the assay with dynamic microtubules in the presence of 30 nM ASPM. White arrows indicate the sites where severing events occur. Time represented as min:sec. f, n = 64 (WT), 59 (R615A) and 59 (Y574A) microtubules; g, Data are the mean of 2 experiments. Scale bar, 2 μm. (h–j) 30 nM ASPM F302A/F377A mutant does not recruit p60/p80C to microtubule lattice and does not promote severing. i, n = 62 (WT) and 60 (F302A/F377A) microtubules; j, data are the mean of 2 experiments. Severing frequency data for WT in panels g and j were replotted from Fig. 7f (30 nM). (k–m) 5 nM ASPM F302A/F377A mutant does not recruit p60/p80C to dynamic microtubule minus ends and does not induce their blocking. l, n = 19 (WT) and 29 (F302A/F377A) microtubules; m, n = 19 (WT) and 33 (F302A/F377A) microtubules. Scale bars, horizontal, 2 μm; vertical, 1 min. Data represent mean ± s.d. Source data for panels f, g, i, j, l and m can be found in Supplementary Table 5.
Supplementary Figure 7 Purified proteins used for in vitro reconstitution experiments.
(a) Coomassie blue stained gels with strep-GFP tagged ASPM, Asp and ASPM-1 proteins purified from transiently transfected HEK293T cells. The bands corresponding to purified full-length proteins are marked with red asterisks. (b) Coomassie blue stained gels with p60/strep-SNAP-p80C wild-type and mutants, p60N + L/strep-GFP-p80C and p60N + L/strep-SNAP-p80C purified from HEK293T cells and strep-p60/6xHis-GFP-p80C purified from E. coli.
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Reduced spindle flux in ASPM and katanin knockout cells.
Photoactivation of PA-GFP-α-tubulin in control (left), ASPM knockout (middle) and katanin knockout (right) U2OS metaphase cells. Images were collected using a spinning disk microscope at 2 s interval. Video is sped up 60 times. Time is shown in the format min:sec. (MOV 5999 kb)
Overexpressed katanin p60/p80 complex tracks and bends microtubule ends in cells.
MRC5 cells were co-transfected with GFP-p60, p80 (dark) and EB3-TagRFP. Images were collected using a TIRF microscope in stream mode (2 frames/s). Video is sped up 15 times. Time is shown in the format min:sec. (MOV 1481 kb)
Katanin p60/p80C severs dynamic microtubules at 300 nM in vitro.
Microtubules were first polymerized in the tubulin polymerization reaction mix (20 μM unlabeled tubulin and 0.5 μM X-rhodamine-tubulin in MRB80 buffer supplemented with 50 mM KCl). Subsequently, the tubulin polymerization reaction mix supplemented with 300 nM p60/SNAP-Alexa647-p80C and 1 mM ATP was flowed into the reaction chamber. Images were collected using a TIRF microscope at a 3 s interval. Video is sped up 15 times. Time is shown in the format min:sec. (MOV 3936 kb)
Katanin p60N + L/p80C bends and breaks a microtubule end in vitro.
Microtubules were polymerized in the presence of 1 μM p60N + L/GFP-p80C, 20 μM unlabeled tubulin and 0.5 μM X-rhodamine-tubulin in MRB80 buffer supplemented with 50 mM KCl. Images were collected using a TIRF microscope at 2 s interval. Video is sped up 30 times. Time is shown in the format min:sec. (MOV 181 kb)
30 nM ASPM and 25 nM katanin p60/p80C sever dynamic microtubules in vitro.
Microtubules were first polymerized in the tubulin polymerization reaction mix (20 μM unlabeled tubulin and 0.5 μM X-rhodamine-tubulin in MRB80 buffer supplemented with 50 mM KCl). Subsequently, tubulin polymerization reaction mix supplemented with 30 nM ASPM, 25 nM p60/SNAP-Alexa647-p80C and 1 mM ATP was flowed into the reaction chamber. Images were collected using a TIRF microscope at a 3 s interval. Video is sped up 15 times. Time is shown in the format min:sec. (MOV 3526 kb)
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Jiang, K., Rezabkova, L., Hua, S. et al. Microtubule minus-end regulation at spindle poles by an ASPM–katanin complex. Nat Cell Biol 19, 480–492 (2017). https://doi.org/10.1038/ncb3511
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DOI: https://doi.org/10.1038/ncb3511
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