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CLIPs and CLASPs and cellular dynamics

Nature Reviews Molecular Cell Biology volume 6, pages 487–498 (2005)Cite this article

Key Points

  • Microtubules are polar, filamentous fibres. They are dynamic structures that are important for widely different processes, which include mitosis, cell migration, neuronal differentiation and transport of cargo.

  • The dynamic properties of microtubules are, in part, regulated by plus-end tracking proteins (+TIPs), which associate with the distal ends of microtubules. Many of the +TIPs interact with each other as well as with microtubules.

  • Different mechanisms account for the specific association of +TIPs with the microtubule end. Among these are 'treadmilling', motor-protein-mediated delivery and 'hitch hiking'.

  • Cytoplasmic linker proteins (CLIPs) interact with CLIP-associating proteins (CLASPs) and both are conserved +TIPs. CLIPs and CLASPs might cooperate to regulate cellular asymmetry.

  • CLIP170 and CLIP115 are homodimers that contain very similar N-terminal microtubule-binding motifs, an elongated coiled-coil domain, but differing C termini. They are general promoters of microtubule growth.

  • The structure of CLASPs has been less well defined. CLASPs are regulatable proteins and are involved in stabilizing a subset of microtubules at highly specific cellular sites in response to signalling cues. These sites include mitotic kinetochores, as well as microtubule ends at the leading edge of fibroblasts and neuronal growth cones.

Abstract

The dynamic properties of microtubules are regulated by plus-end tracking proteins (+TIPs), which associate with the distal ends of microtubules. Among the +TIPs are cytoplasmic linker proteins (CLIPs), which promote microtubule growth and regulate dynein–dynactin localization, and CLIP-associating proteins (CLASPs), which stabilize specific subsets of microtubules on reception of signalling cues. CLIPs and CLASPs interact and cooperate to direct the microtubule network, thereby regulating cellular asymmetry.

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Figure 1: Organization of the microtubule network in different model systems.
Figure 2: CLIPs.
Figure 3: Mechanisms of +TIP localization.
Figure 4: CLASPs.
Figure 5: Cell polarity cues can stabilize microtubules through +TIPs.

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Acknowledgements

I would like to thank past and present members of my laboratory and colleagues in the field for stimulating discussions. They have helped to shape this review. Work in my laboratory is supported by grants from the Netherlands Organization for Scientific Research, the Dutch Cancer Society and the Ministry of Economic Affairs.

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Authors and Affiliations

  1. Department of Cell Biology and Genetics, Erasmus Medical Centre, P.O. Box 1738, Rotterdam, 3000 DR, The Netherlands

    Niels Galjart

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  1. Niels Galjart
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Supplementary information

41580_2005_BFnrm1664_MOESM1_ESM.mov

S1 (movie) | GFP–CLIP170 in 3T3 fibroblasts. 3T3 fibroblasts that express low levels of inducible GFP–CLIP170 were maintained at 37°C in normal culture medium and were analysed by confocal microscopy. The movie contains 25 images, acquired every 2 seconds. Dashes of GFPndash;CLIP170 display a cometlike shape with a sharp and brightly fluorescent front that points towards the microtubule plus end. Most comets build up in the centrosomal region. They move toward the cell periphery, where they disappear. Images were acquired by T. Stepanova, Department of Cell Biology and Genetics, Erasmus Medical Centre, the Netherlands. (MOV 305 kb)

41580_2005_BFnrm1664_MOESM2_ESM.mov

S2 (movie 2007 KB) | EB3–GFP movement in transfected neurons and glia. Hippocampal cultures were infected with a virus that expresses EB3–GFP. Cultures were imaged as in Movie 1 and the movie contains 100 images. Notice how the axon from a hippocampal neuron makes contact with a glial cell. The movie shows that neuronal microtubule 'comets' move slower than glial ones, indicating slower microtubule growth rates in neurons. Images were acquired by T. Stepanova, Department of Cell Biology and Genetics, Erasmus Medical Centre, The Netherlands. (MOV 305 kb)

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DATABASES

Swiss-Prot

ACF7

CLASP1

CLASP2

CLIP115

CLIPR59

CYLD

EB1

IQGAP1

LIS1

restin

Interpro

CAP-Gly

Flybase

CLIP190

Orbit

Short stop

Saccharomyces genome database

Bik1

Bim1

Nip100

Pac1

S. pombe gene database

Mal3

Ssm4

Tip1

FURTHER INFORMATION

Scansite

Glossary

GREEN FLUORESCENT PROTEIN

(GFP). Fluorescent protein cloned from the jellyfish Aequoria victoria. The most frequently used mutant, EGFP, is excited at 488 nm and has an emission maximum at 510 nm.

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.

COILED-COIL DOMAIN

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

MICROTUBULE-ORGANIZING CENTRE

(MTOC). Also called the centrosome or spindle-pole body, this structure nucleates and organizes microtubules.

β-SHEET

An element of protein secondary structure in which hydrogen bonds between the backbones of the same or different polypeptides stabilize arrays of parallel chains that can form larger elements resembling sheets.

ZINC KNUCKLE

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

ATOMIC FORCE MICROSCOPY

A microscopy technique that nondestructively measures the forces (at the atomic level) between a sharp probing tip (which is attached to a cantilever spring) and a sample surface. The microscope images structures at the resolution of individual atoms.

FLUORESCENCE RESONANCE ENERGY TRANSFER

(FRET). The non-radiative transfer of energy from a donor fluorophore to an acceptor fluorophore, which occurs when the donor and acceptor fluorophore are typically <80 Ă… apart. FRET will only occur between fluorophores in which the emission spectrum of the donor has a significant overlap with the excitation wavelength of the acceptor.

PROCESSIVITY

The ability of a motor protein to move long distances without dissociating.

KINETOCHORE

A large multiprotein complex that assembles on the centromere of the chromosome and links the chromosome to the microtubules of the mitotic spindle.

DENDRO-DENDRITIC GAP JUNCTIONS

Small pores, formed by connexins in the membranes of two adjacent cells, that allow passage of low molecular-weight compounds from one cell to the other. Dendro–dendritic gap junctions form between two dendrites.

LIPID RAFTS

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

TREADMILLING

A special state in polymer dynamics, when monomer addition at one end occurs at the same rate as monomer dissociation at the other end, which keeps the polymer length unchanged.

CATASTROPHE

The transition from microtubule growth to shortening.

DOMINANT NEGATIVE

A defective protein that retains interaction capabilities and so competes with normal proteins, thereby impairing protein function.

RNA INTERFERENCE

(RNAi). A form of post-transcriptional gene silencing in which expression or transfection of double-stranded RNA induces degradation — by nucleases — of the homologous endogenous transcripts. This mimics the effect of the reduction, or loss, of gene activity.

SCHMOOING

A change in cell appearance from round to pear-shaped in a yeast cell.

PALMITOYLATION

Covalent attachment of a palmitate (16-carbon saturated fatty acid) to a cysteine residue through a thioester bond.

HEAT REPEAT

A tandemly repeated, 37–47-amino-acid module that occurs in several cytoplasmic proteins. Arrays of HEAT repeats form a rod-like helical structure and are thought to function as protein–protein interaction surfaces.

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 ÎĽm into the lamellipodium.

SPINDLE POLE

The yeast equivalent of the centrosome that nucleates microtubules, including those that will form the spindle.

SPECTRAPLAKINS

Plakins that contain spectrin repeats. Plakins are proteins that crosslink cytoskeletal filaments and attach them to membrane-associated complexes at cell junctions.

FORMINS

A family of proteins that contain a formin-homology-2 (FH2) domain. They can promote actin assembly.

RHO-FAMILY GTPASES

Ras-related GTPases that are involved in controlling the dynamics of the actin cytoskeleton.

EFFECTOR

A protein or protein complex that binds the GTPase directly and in a GTP-dependent manner, and is required for the downstream function determined by that GTPase.

GUANINE NUCLEOTIDE-EXCHANGE FACTOR

A protein that activates a specific small GTPase by catalysing the exchange of bound GDP for GTP.

VISCERAL ENDODERM CELLS

Cells that delineate the yolk sac cavity together with parietal endoderm cells in the egg cylinder stage of the mammalian embryo.

NOCODAZOLE

A microtubule-depolymerizing drug.

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Galjart, N. CLIPs and CLASPs and cellular dynamics. Nat Rev Mol Cell Biol 6, 487–498 (2005). https://doi.org/10.1038/nrm1664

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