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Microtubule +Tips at a Glance Anna Akhmanova and Michel O

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Microtubule +Tips at a Glance Anna Akhmanova and Michel O Cell Science at a Glance 3415 Microtubule +TIPs at a modifications of microtubules’ by Dorota Wloga and diverse group of proteins that are distinguished Jacek Gaertig (J. Cell Sci. 123, pp. 3447-3455). by their specific accumulation at microtubule glance plus ends (Mimori-Kiyosue et al., 2000; Perez et Microtubules are highly dynamic hollow tubes al., 1999; Schuyler and Pellman, 2001). +TIPs Anna Akhmanova1 and Michel O. that are involved in many vital cellular typically target growing but not shrinking Steinmetz2 activities, including maintenance of cell shape, microtubule ends; however +TIP association 1 Department of Cell Biology, Erasmus Medical division, migration and intracellular transport. with depolymerizing ends can occur and, in Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands They are assembled from heterodimers of - some organisms such as budding yeast, is even 2Biomolecular Research, Structural Biology, Paul and -tubulin that align in a head-to-tail fashion. quite common. In this Cell Science at a Glance Scherrer Insititut, CH-5232 Villigen PSI, Switzerland Microtubules are, thus, intrinsically polar article we review and illustrate the current ([email protected]; [email protected]) because they contain two structurally distinct knowledge of these peculiar proteins, ends: a slow-growing minus end, exposing - summarize their structural and functional Journal of Cell Science 123, 3415-3419 © 2010. Published by The Company of Biologists Ltd tubulin subunits; and a fast-growing plus end, properties, and discuss the proposed molecular doi:10.1242/jcs.062414 exposing -tubulin subunits (for a review, see mechanisms that they use to track microtubule Nogales and Wang, 2006). In mammalian cells, ends. This article is part of a Minifocus on microtubule dynamics. For further reading, please see related microtubule minus ends are often stably articles: ‘Kinesins at a glance’ by Sharyn A. Endow anchored, whereas the plus ends are highly Classification of +TIPs et al., (J. Cell Sci. 123, pp. 3420-3424), ‘Tubulin dynamic and stochastically switch between The first reported +TIP was cytoplasmic linker depolymerization may be an ancient biological motor process’ by J. Richard McIntosh et al. (J. Cell Sci. phases of growth and shrinkage, a process that is protein of 170 kDa (CLIP-170, officially known 123, pp. 3425-3434), ‘Towards a quantitative powered by GTP hydrolysis. as CLIP1) (Perez et al., 1999). Since its understanding of mitotic spindle assembly and Microtubule plus-end tracking proteins discovery, more than 20 different +TIP families mechanics’ by Alex Mogilner and Erin Craig (J. Cell Sci. 123, pp. 3435-3445) and ‘Post-translational (+TIPs) are a structurally and functionally have been identified. +TIPs are usually Microtubule +TIPs at a Glance Anna Akhmanova and Michel O. Steinmetz +TIP classification What is a +TIP? +TIP functions EB proteins CAP–Gly proteins +TIPs localize to and track dynamic MT plus ends Microtubule dynamics CAP–Gly EBH Coiled coil ZnF +TIP that tracks only Growing MT GTP Shrinking MT Polymerization Depolymerization EB CH CLIP170 growing MT plus ends β β (XMAP215, EB1) (MCAK) Rescue Coiled EEY/F Basic-S/P EEY/F (e.g. EB1, CLIP-170) Plus end α α (CLIP-170, CLASP) coil p150glued +TIP that tracks growing GDP SxIP proteins and shrinking MT plus Coiled 15/20 aa ends (e.g. Dam1, Kar9) Catastrophe SxIP Rescue coil Helical repeats β (MCAK) Basic-S/P Stabilization APC GTP-tubulin α (CLASP, APC, MACF) Arm SAMP SxIP β Catastrophe Journal of Cell Science Plakin Spectrin EF MACF CH α GDP-tubulin GAS2 SAM SxIP Further examples: CLASP, p140Cap, melanophilin In vitro, some +TIPs can STIM1 Interactions with cellular structures RhoGEF2, CDK5RAP2, TIP150, navigator bind to growing but not EF TM Minus end shrinking MT minus ends Cortex Endoplasmic reticulum (CLASP, APC, MACF, CLIP-170, EB1, (EB1, STIM1) TOG proteins Other proteins dynein, dynactin, LIS1) TOG Basic-S/P Helical Multimeric XMAP215 Dam1 complex of 10 proteins +TIP localization SxIP CLASP LisH WD40 Lis1 +TIP distribution in mammalian interphase cells TOG-like Live image of a Helical Monkey Kar9 kidney cell human lung Motor proteins Basic-S/P stained for fibroblast expressing endogenous an MT marker Kinesin Basic-S/P SxIP EB1 (mCherry-α-tubulin, F-actin Vesicles Tea2 Ncd MCAK red) and a +TIP (MACF, CLASP, APC, CLIP-170, Kar9, (dynein, dynactin, RhoGEF2, p140Cap) CLIP-170, Melanophilin) Helical AAA marker (EB3-GFP, Dynein HC green) Coiled coil +TIPs that belong to several classes: CLASP (SxIP, TOG), MCAK (SxIP, motor) +TIP interactions Microtubule plus-end tracking mechanisms Kinetochores (Dam1, CLASP, CLIP-170, APC, EB1, SxIP proteins CAP-Gly-EEY/F 3D diffusion dynein, dynactin, LIS1, MCAK) Proteins with Autonomous (STIM1) Microtubules APC in cytoplasm 2D diffusion unknown Microtubule +TIP (Ncd, Klp2) Tyr Lattice- (RhoGEF2, Lis1) in membrane EB-binding MACF Glu maturation- mechanisms CH CH Melanophilin Non-autonomous induced release Hitchhiking XMAP215 EB MCAK +TIPs Kar9 STIM1 Kinesin-based transport EBH Tea2 TIP150 Glu (Tea2–Tip1, Kip2–Bik1) Kinesin Ncd EEY/F RhoGEF2 Co-polymerization Centrosome EBH-SxIP CDK5RAP2 (XMAP215, EB1, CLASP, APC, p140Cap GTP-tubulin dynein, dynactin, Lis1, FOP, CDK5RAP2) CLASP Pro CAP-Gly GDP-tubulin 1D lattice diffusion proteins (MCAK, XMAP215) Processive Ile Fast end tracking Lipid bilayer Dynein p150glued x Recognition exchange (XMAP215, Dam1) Ser of composite (EB1, Proteins in parentheses +TIP/tubulin-binding CLIP-170) indicate selected examples sites (CLIP-170, MCAK) of +TIPs using a particular Recognition of specific Lis1 CLIP-170 mechanism plus-end structure (EB1) Abbreviations: AAA, ATPase family associated with various cellular activities; APC, adenomateous polyposis crosslinking factor; MCAK, mitotic centromere-associated kinesin; MT, microtubule; Ncd, non-claret disjunctional; coli protein; Arm, armadillo repeat; basic-S/P, sequence regions enriched in basic, serine and proline residues; p140Cap, p130Cas-associated protein of 140 kDa (also known as SRCIN1, SRC kinase signaling inhibitor 1, SNIP, CAP-Gly, cytoskeleton-associated protein glycine-rich; CDK5RAP2, CDK5 regulatory subunit- associated protein 2; SNAP-25-interacting protein); RhoGEF2, Rho-type guanine nucleotide-exchange factor 2; SAM, sterile α-motif CH, calponin homology; CLASP, CLIP-associated protein; CLIP-170, cytoplasmic linker protein of 170 kDa; Dam1, domain; SAMP, Ser-Ala-Met-Pro repeat; STIM1, stromal interaction molecule 1; SxIP, Ser-x-Ile-Pro tetrapeptide DUO1- and MPS1-interacting protein 1; EB, end-binding protein; EBH, EB homology; EEY/F, C-terminal Glu-Glu- motif, where x denotes any amino acid residue; +TIP, microtubule plus-end tracking protein; TIP150, +TIP of 150 Tyr/Phe tripeptide motif; EF-hand, Ca2+-binding motif; FOP, FGFR1 oncogene partner; Gas2, growth-arrest-specific kDa; TM, transmembrane domain; TOG, named after the discovery in human chTOG; WD40, ~40 amino acid protein 2; HC, heavy chain; Lis1, lissencephaly-1 protein; LisH, Lis1 homology; MACF, microtubule-actin motifs, often terminating in a Trp-Asp dipeptide; XMAP215, microtubule-associated protein of 215 kDa. © Journal of Cell Science 2010 (123, pp. 3414–3418) (See poster insert) 3416 Journal of Cell Science 123 (20) multidomain and/or multisubunit proteins that motif Ser-x-Ile-Pro (SxIP, where x denotes any display affinities in the low micromolar range range in size from a few hundred up to amino acid), which is specifically recognized by (Gupta et al., 2009; Mishima et al., 2007; thousands of residues. They can be cytoplasmic the EBH domain of EB proteins (Honnappa Weisbrich et al., 2007). or membrane bound, and comprise motor and et al., 2009). Prominent examples of this diverse EB proteins are now generally accepted to non-motor proteins (for a review, see class of +TIPs are the adenomatous polyposis represent core components of +TIP networks Akhmanova and Steinmetz, 2008). +TIPs can be coli (APC) tumour suppressor, the spectraplakin because they autonomously track growing classified on the basis of prominent structural microtubule–actin crosslinking factor (MACF) microtubule plus ends independently of any elements that enable them to interact with each and the mitotic centromere-associated kinesin binding partners (Bieling et al., 2008; Bieling et other and with microtubules; however, in some (MCAK). Because SxIP motifs are very short, al., 2007; Dixit et al., 2009; Komarova et al., cases, +TIPs combine features characteristic of they can be easily acquired or lost during 2009; Zimniak et al., 2009). Moreover, EB several +TIP classes. evolution; for example, CDK5RAP2, a protein proteins directly associate with almost all other End-binding (EB) family proteins contain a implicated in microcephaly, contains an EB1- known +TIPs and, by doing so, target them to highly conserved N-terminal domain that adopts binding SxIP motif in humans and dogs but not growing microtubule plus ends (for reviews, see a calponin homology (CH) fold (Korenbaum in rodents (Fong et al., 2009). Akhmanova and Steinmetz, 2008; Slep, 2009b). and Rivero, 2002) and is responsible for Proteins with TOG or TOG-like domains SxIP motifs act as a general ‘microtubule tip microtubule binding (Hayashi and Ikura, 2003). (named after their discovery in the protein ch- localization signal’ (MtLS) by interacting with In mammalian EB1 and EB3, a CH domain with TOG) include members of the XMAP215/Dis1 the EBH domain of EB proteins (Honnappa the adjacent linker sequence is sufficient for
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