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  • Review Article
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Tracking the ends: a dynamic protein network controls the fate of microtubule tips

Key Points

  • Plus-end tracking proteins (+TIPs) are distinguished by their ability to specifically accumulate at the growing ends of microtubules.

  • +TIPs include several structurally unrelated and evolutionary conserved protein families of microtubule-associated proteins (MAPs).

  • Several relatively small protein modules and linear sequence motifs, including calponin homology domains, CAP-Gly domains, C-terminal acidic-aromatic motifs, basic, Ser-rich sequence stretches and coiled-coil domains are present in many +TIPs and mediate interactions of these proteins with each other and with microtubules. These interactions are usually of moderate affinity allowing dynamic +TIP networks to remodel rapidly.

  • Although many +TIPs directly interact with each other, they can exert different and sometimes opposite effects on microtubule dynamics, such as microtubule stabilization or destabilization.

  • Molecular mechanisms that underlie microtubule plus-end tracking phenomena are not yet fully resolved. They probably involve the recognition of some specific tubulin sites, which are exposed only at the growing ends of microtubules but are shielded within the microtubule lattice.

  • +TIPs may be recruited to microtubule ends by diffusion through cytoplasm or along the microtubule lattice; by co-polymerization with tubulin subunits or by motor-mediated transport along the microtubules.

  • +TIP accumulation at the growing microtubule ends can serve both structural and signalling purposes. +TIPs can affect the shape and positioning of microtubule networks by regulating microtubule dynamics, by linking microtubules to different cellular structures and by exerting forces at the microtubule ends. Therefore, +TIPs are profoundly involved in many processes such as cell division, polarity and differentiation, and morphogenesis.

Abstract

Microtubule plus-end tracking proteins (+TIPs) are a diverse group of evolutionarily conserved cellular factors that accumulate at the ends of growing microtubules. They form dynamic networks through the interaction of a limited set of protein modules, repeat sequences and linear motifs that bind to each other with moderate affinities. +TIPs regulate different aspects of cell architecture by controlling microtubule dynamics, microtubule interactions with cellular structures and signalling factors, and the forces that are exerted on microtubule networks.

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Figure 1: Localization of plus-end tracking proteins in mammalian cells.
Figure 2: Structural classification of plus-end tracking proteins.
Figure 3: Structure of plus-end tracking protein elements and their interaction modes.
Figure 4: Mechanisms of microtubule plus-end tracking.
Figure 5: The dynamic interaction network of plus-end tracking proteins.

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Acknowledgements

We thank I. Grigoriev for contributing live cell images illustrating microtubule plus-end tracking in mammalian cells. We are indebted to Y. Barral, P. Meraldi, R. Jaussi, A. Weisbrich and S. Honnappa for critical reading of the manuscript. M.O.S. acknowledges support by the Swiss National Science Foundation (SNF).

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Supplementary information

Supplementary information S1(Movie)

Live imaging of a peripheral edge of a human lung fibroblast expressing mCherry–α–tubulin (a red microtubule marker), and the plus–end tracking protein EB3 (conjugated to green fluorescent protein). Red and green images were obtained simultaneously with a wide–field microscope with a 3 s interval. The movie includes 60 frames projected at 15 frames/s. (MOV 1093 kb)

Supplementary information S2(Table) (PDF 240 kb)

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FURTHER INFORMATION

Anna Akhmanova’s homepage

Michel Steinmetz’s homepage

COILS

PredictProtein

SUPPLEMENTARY INFORMATION

S1 (movie)

S2 (table)

Glossary

Microtubule plus end

The microtubule end that grows fast in vitro. In vivo, plus ends are the dynamic ends of microtubules that alternate between periods of growth and shrinkage and are often directed towards the cell surface.

Calponin-homology (CH) domain

An actin-binding domain of approximately100 residues, which is common to many actin-binding proteins, including cytoskeletal and signal-transduction proteins. Tubulin-binding CH domains have recently also been found in several microtubule-associated proteins.

Lattice seam

A discontinuity in the surface of the microtubule wall.

Coiled-coil domain

A protein structural motif that mediates subunit oligomerization. Coiled coils contain between two and five α-helices that twist around each other to form a supercoil.

α-helix

An element of the secondary structure of a protein in which hydrogen bonds located along the backbone of a single polypeptide cause the chain to form a right-handed helix.

End binding homology (EBH) domain

A50 amino-acid domain found at the C terminus of EB proteins. It comprises a pair of helix-loop-helix segments forming an antiparallel four-helix bundle. A deep hydrophobic cavity on the surface of the EBH domain serves as an interaction site for binding partners.

EEY/F sequence motif

A highly specific and conserved sequence motif found at the C terminus of α-tubulin, EB and CLIP170. The EEY/F motif is the target of CAP-Gly domains.

Cytoskeleton-associated protein Gly-rich (CAP-Gly) domain

A domain of 70-residues that is characterized by conserved Gly residues, which are involved in shaping the loop regions of the globular fold. CAP-Gly domains contain a hydrophobic cavity responsible for binding to C-terminal EEY/F motifs.

Kymograph

A graphical representation of spatial position over time.

Zinc knuckle

A protein domain in which specifically positioned Cys and His residues coordinate the binding of a zinc ion, thereby generating a structural conformation (the 'knuckle') that is capable of protein–protein and protein–DNA interactions.

Guanine nucleotide-exchange factor (GEF).

A protein that facilitates the exchange of GDP for GTP in the nucleotide-binding pocket of a GTP-binding protein.

TOG domain

A HEAT repeat containing tubulin-binding domain named after its discovery in the human MAP chTOG (colonic and hepatic tumour-overexpressed gene, the homologue of the Xenopus protein XMAP215).

HEAT repeat

A module containing 37–47 amino acids; named after its discovery in huntingtin elongation factor-3, a subunit of protein phosphatase-2A and protein kinase mammalian target of rapamycin. Arrays of HEAT repeats form rod-like helical structures that participate in protein–protein interactions.

LIS homology (LISH) domain

A 60-residue domain that is seamlessly followed by a short coiled-coil domain that mediates parallel dimerization. The two pairs of α-helices of LisH assemble into an antiparallel four-helix bundle.

WD40 repeat

Protein motif composed of a 40-amino-acid repeat that forms a blade of a characteristic β-propeller structure. Proteins that contain WD40 repeats participate in G-protein-mediated signal transduction, transcriptional regulation, RNA processing and regulation of vesicle formation and trafficking.

β-Propeller

A compact structural domain, or protein-folding pattern, in which similarly sized β-sheets are stacked and offset into a cylinder, so that they resemble the blades of a propeller.

Dynein

A large, minus-end-directed multisubunit microtubule motor protein that is involved in several cellular processes.

Dynactin

An accessory multi-subunit complex of dynein that is important for the activation and interaction of dynein with its cargo.

Minus end

The slow-growing microtubule end in vitro. Minus-ends usually do not grow in vivo; they serve as sites of depolymerization or are stabilized and are often associated with the centrosome in the cell interior.

Kinesin

A microtubule-based molecular motor, most often directed towards the plus end of microtubules.

Type V myosin

Subclass of the myosin protein family of actin-dependent motor proteins, required for transport of vesicles or messenger RNA cargo.

Dam1/DASH complex

Multi-subunit protein complex that forms rings around microtubules. It may provide a dynamic linkage at depolymerizing or polymerizing microtubule ends for force generation.

Processive transport

Long-distance motor-based movement along a cytoskeletal filament without dissociation.

Leading edge

The thin margin of a lamellipodium that spans the area of the cell from the plasma membrane to a depth of about 1 μm into the lamellipodium. It is usually located at the front of a migrating cell.

Growth cone

Motile tip of the axon or dendrite of a growing nerve cell, which spreads out into a large cone-shaped appendage.

Microtubule-organizing centre

(MTOC).The structure that nucleates and organizes microtubules. It often contains the centrosome or spindle-pole body.

Catastrophe

The transition from microtubule growth to shortening.

Rescue

The transition from microtubule shortening to growth.

Optical tweezers

An instrument used for the manipulation of individual protein molecules. The method is based on the radiation pressure of light.

Kinetochore

Specialized regions on chromosomes that are connected to microtubules and motor proteins during cell division in eukaryotes. Kinetochores function in the separation of chromosome pairs.

Melanosome

Organelles that contain melanin, a common light-absorbing pigment.

Lipid raft

Lateral aggregates of cholesterol and sphingomyelin that are thought to occur in the plasma membrane.

Focal adhesion

Integrin-mediated, cell–substrate adhesion structures that anchor the ends of actin filaments (stress fibres) and mediate strong attachments to substrates. They also function as integrin signalling platforms.

Cadherin

A cell-type-specific, calcium-dependent transmembrane adhesion protein. Cadherins promote homophilic binding and are preferentially located at adherens junctions.

Gap junction

A junction between two cells that consists of pores that allow passage of molecules (up to 1 kDa).

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Akhmanova, A., Steinmetz, M. Tracking the ends: a dynamic protein network controls the fate of microtubule tips. Nat Rev Mol Cell Biol 9, 309–322 (2008). https://doi.org/10.1038/nrm2369

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