Cell Biology: Chapter 6 — Cytoskeleton and movement

6.1 Three polymers #

6.1.1 Why a cytoskeleton #

Eukaryotic cells are too large, and too often asymmetric, to rely on a cell wall or on diffusion for organisation. The cytoskeleton is a set of protein polymers that give shape, move organelles, pull chromosomes, and, in muscle and crawling cells, move the whole cell. Prokaryotes have related but simpler cytoskeletal proteins (FtsZ is a tubulin homologue, MreB is an actin homologue). The eukaryotic elaboration is in the motors and the regulation.

6.1.2 Comparison #

Intermediate filaments are the least dynamic and the most tissue-specific. A keratin stain identifies an epithelial tumour; a vimentin stain points toward a mesenchymal one. Lamins are the nuclear members of the family and are universal in animals. Plants largely lack intermediate-filament equivalents of the cytoplasmic kind.

6.2 Actin and microfilaments #

The study of Actin and microfilaments provides fundamental principles governing cellular architecture, molecular interactions, and physiological regulation.

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6.2.1 Assembly #

G-actin adds to both ends of a filament, faster at the barbed end. Soon after incorporation, ATP is hydrolysed. The filament then has ADP-actin in its middle and a cap of newer ATP-actin (or ADP-Pi-actin) at the ends. If the free monomer concentration is between the critical concentrations of the two ends, the barbed end grows while the pointed end shrinks. Subunits treadmill through the filament. This is the same logic as microtubule dynamic instability, reached by a different kinetic regime.

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Cells never rely on the naked polymer. Formins nucleate linear filaments. The Arp2/3 complex nucleates branches at 70 degrees, which builds the dendritic networks of the leading edge. Capping proteins stop growth. Cofilin severs old ADP-actin filaments and speeds turnover. Profilin recharges monomers with ATP and hands them to barbed ends. Cross-linkers decide the architecture: fimbrin and villin make tight bundles (microvilli), spectrin makes networks (the red-cell cortex), and filamin makes gels.

6.2.2 Myosin and muscle #

Myosins are actin motors that convert ATP hydrolysis into walking or into the pulling of a filament. Conventional myosin II, the muscle motor, has two heads and a long coiled-coil tail. Tails pack into thick filaments. The head binds actin, pulls, and releases, repeatedly. The duty cycle is short, so many heads must work asynchronously on one thick filament.

The sarcomere is the unit.

• Thin filaments of actin are anchored at the Z disc, with their barbed ends at the Z disc, and are decorated with tropomyosin and troponin.
• Thick filaments of myosin II occupy the centre (A band), with heads at both ends and a bare zone in the middle.
• At rest, tropomyosin blocks the myosin-binding sites on actin.

Excitation–contraction coupling connects a nerve impulse to this machine. The action potential spreads into T-tubules, opens voltage sensors (dihydropyridine receptors), and those open ryanodine receptors in the sarcoplasmic reticulum. Ca2+ floods the cytosol, binds troponin C, tropomyosin shifts, and myosin heads bind actin. The filaments slide. The sarcomere shortens. The A band stays the same length, which is the observation that established the sliding-filament mechanism: the filaments do not shorten; they overlap more. Pumping Ca2+ back into the sarcoplasmic reticulum ends the contraction.

Smooth muscle and non-muscle cells use myosin II differently. Phosphorylation of the regulatory light chain by myosin-light-chain kinase, activated by Ca2+-calmodulin, turns the motor on. There is no troponin and no sarcomere.

Other myosins carry cargo. Myosin V walks processively toward the barbed end and delivers vesicles. Myosin VI is unusual in walking toward the pointed end.

6.3 Microtubules #

6.3.1 The organising centre and dynamic instability #

αβ-tubulin adds so that β-tubulin faces the plus end. In animal cells the minus ends are usually anchored at the centrosome, a pair of centrioles (each a cylinder of nine triplet microtubules) surrounded by pericentriolar material that contains γ-tubulin ring complexes. Those rings nucleate microtubules. Flowering plants and many fungi have no centrioles and still organise spindles, so centrioles are one solution, not the only one. Centrioles become basal bodies when they move to the membrane and grow a cilium.

Microtubules show dynamic instability. A growing plus end is protected by a GTP cap. If hydrolysis catches up, the protofilaments peel outward and the microtubule catastrophically shrinks, then may be rescued. The cell explores space with growing microtubules and stabilises the ones that hit a useful target, such as a kinetochore or the cell cortex. This search-and-capture behaviour builds the spindle.

6.3.2 Motors and intracellular transport #

Kinesin-1 walks toward the plus end, hand over hand, one ATP per 8 nm step (the length of a tubulin dimer). Cytoplasmic dynein, with the dynactin complex, walks toward the minus end. In an axon, microtubules are oriented plus-end-out, so kinesin carries cargo to the synapse (anterograde) and dynein returns cargo to the cell body (retrograde). A single axon can be a metre long in a human motor neuron. Diffusion of a vesicle over that distance would take years. Motors take it in days, and for some cargo in hours. Neurodegenerative mutations in motors and in the tracks are one clinical reading of this dependence.

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Cilia and flagella (the eukaryotic kind) are a specialised microtubule machine.

• The axoneme is nine outer doublet microtubules around a central pair (9 + 2), arising from a basal body that has nine triplets and no central pair (9 + 0).
• Dynein arms on each doublet walk on the neighbouring doublet. Because the doublets are tied together by nexin links and a spoke system, walking bends the cilium instead of sliding it apart.
• The bend propagates, which gives the whip-like or the breast-stroke waveform.
• Primary cilia, which most mammalian cells have, are usually non-motile 9 + 0 sensory antennae. Defects in them cause a set of diseases grouped as ciliopathies, including polycystic kidney disease.

Bacterial flagella, as noted in Chapter 1, are a different structure with a rotary motor.

6.4 Intermediate filaments and whole-cell movement #

The study of Intermediate filaments and whole-cell movement provides fundamental principles governing cellular architecture, molecular interactions, and physiological regulation.

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6.4.1 Mechanical integration #

Intermediate filaments link to desmosomes and hemidesmosomes (Chapter 5) and to the nuclear lamina. They distribute stress so that a tissue stretches instead of tearing. Epidermolysis bullosa simplex, caused by keratin mutations, produces fragile skin that blisters from mild friction: the cells rupture below the nucleus, exactly where the keratin network failed. There are no intermediate-filament motors. Other filaments do the moving; intermediate filaments hold.

6.4.2 Cell crawling #

A fibroblast or a neutrophil crawls in four overlapping steps.

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1. Protrusion. At the leading edge, Arp2/3 builds a branched actin network that pushes the membrane outward as a lamellipodium. Bundled actin makes finger-like filopodia that explore.

2. Adhesion. Integrins in the new membrane bind the ECM and form focal contacts, then focal adhesions.

3. Traction. Actin–myosin contraction pulls the cell body forward, and myosin helps disassemble adhesions at the rear.

4. Deadhesion at the tail. Old adhesions release so the rear can follow.

Polarity of crawling is set by signalling, often by Rho-family GTPases: Rac promotes the branched network of the leading edge, Cdc42 promotes filopodia, and Rho promotes stress fibres and contraction. Bacteria such as Listeria hijack the same Arp2/3 machinery: a bacterial surface protein recruits it, an actin comet tail grows, and the bacterium is pushed through the cytoplasm and into the next cell.

6.5 Key terms, summary, and self-check #

Key terms. Barbed end; treadmilling; Arp2/3; sarcomere; sliding filament; troponin; dynamic instability; centrosome; kinesin; dynein; axoneme; lamellipodium; Rho-family GTPases.

Summary. Actin and microtubules are polar, nucleotide-driven polymers with dedicated motors. Intermediate filaments are apolar mechanical cables. Muscle contraction is Ca2+-regulated sliding of actin and myosin. Ciliary bending is microtubule sliding constrained by links. Crawling is protrusion, adhesion, and traction, organised by small GTPases.

Self-check.

1. Which polymer has no polarity, and what functional consequence does that have for motors?

2. In the sliding-filament mechanism, which band of the sarcomere stays constant in length, and why does that observation rule out filament shortening?

3. Axonal microtubules are plus-end-out. Which motor carries a synaptic vesicle from the cell body to the terminal?

4. Why does a cilium bend instead of the doublets simply sliding off one another?

5. A drug stabilises microtubules and blocks mitosis. Name a drug that does this, and say which stage of mitosis fails first.