Describe the assembly and disassembly process of microtubules

Microtubules are one of the three main components of the cytoskeleton in eukaryotic cells, alongside microfilaments (Actin Filaments) and intermediate filaments. They are long, hollow, cylindrical structures composed of protein subunits called tubulins, and they play a crucial role in various cellular processes, including maintaining cell shape, facilitating intracellular transport, and ensuring proper chromosome segregation during cell division.

They are the largest, with diameters of 25nm compared to actin filaments and intermediate filaments. A microtubule is a dimmer of α- and β-tubulin subunits. Microtubules comprise of 13 protofilaments - alpha (α) tubulin and beta (β) tubulin which are arranged in a helical fashion to form a hollow tube. The lateral interactions of the protofilaments include the wall of the microtubule. A third form of tubulin, gamma (γ) tubulin, is essential for starting microtubule assembly and is mainly localised to the centrosome.

Microtubules within cells are organised in various ways and can form individual filaments, bundles, or networks. In some cases, mitotic spindle are the specialised structures of microtubules during cell division. Microtubules are also structural units for the formation of cilia and flagella.

Assembly and Disassembly Process of Microtubules

The alternating phases of microtubule assembly (known as polymerization) and disassembly (known as depolymerization) are collectively referred to as dynamic instability, was first described by Timothy Mitchison and Marc Kirschner in 1984. This term describes the inherent ability of microtubules to rapidly switch between growth and shrinkage, which is critical for their roles in cellular processes like mitosis, intracellular transport, structural reorganization and formation of specialized structures like cilia and flagella. 

Understanding both assembly and disassembly mechanisms is key to appreciating how microtubules support a broad range of cellular functions.

Assembly (Polymerization) of Microtubules

Microtubule assembly is a finely tuned, multi-step process that begins with nucleation and progresses through elongation and stabilization.

1. Nucleation

The first and most critical step in microtubule polymerization is nucleation, which refers to the formation of a stable microtubule "seed" or nucleus. This step is typically the rate-limiting stage of microtubule formation because the initial assembly of tubulin dimers is energetically unfavorable.
  • Tubulin Dimers: Microtubules are built from α-tubulin and β-tubulin dimers, which polymerize head-to-tail to form linear protofilaments. 13 protofilaments align side by side, forming the hollow cylindrical structure of a microtubule.
  • Microtubule-Organizing Centers (MTOCs): In most cells, microtubule nucleation occurs at MTOCs, such as the centrosome in animal cells. At these sites, the gamma (γ) tubulin ring complex (γ-TuRC) provides a platform for nucleation. The γ-TuRC forms a template that stabilizes the initial assembly of tubulin dimers, facilitating the formation of the microtubule's minus end.
  • γ-Tubulin Ring Complex: The γ-TuRC is a multi-protein complex that provides structural support for nucleation, preventing premature disassembly of the tubulin seed or nucleus. It caps the minus end of the microtubule, allowing growth to occur primarily at the plus end.

2. Elongation

Once nucleation is achieved, the microtubule enters the elongation phase, during which tubulin dimers rapidly add to the growing plus end. The elongation process is driven by GTP-bound tubulin dimers, which preferentially polymerize at the plus end due to the high energy state of GTP-bound tubulin.
  • GTP-Bound Tubulin: Tubulin dimers bind to GTP before being incorporated into the microtubule. The binding of GTP to the β-tubulin subunit increases the affinity between tubulin dimers, driving the polymerization process. As long as GTP-bound tubulin is available, the microtubule will continue to grow.
  • GTP Cap: At the growing plus end, a GTP cap forms, stabilizing the microtubule and preventing disassembly. The GTP cap is made up of tubulin dimers that are still GTP-bound, and it helps maintain the structural integrity of the microtubule. As tubulin dimers move away from the plus end and become part of the microtubule lattice, the GTP is hydrolyzed to GDP, rendering the GDP-bound tubulin less stable.
  • Dynamic Growth: The growth rate of microtubules can vary depending on the concentration of free tubulin dimers and cellular conditions. The plus end is highly dynamic, allowing for rapid extension into the cytoplasm where microtubules can perform functions like vesicle transport and spindle formation during mitosis.

3. Stabilization

Microtubules are inherently unstable structures and require stabilization to function effectively in cells. Several microtubule-associated proteins (MAPs) help stabilize microtubules by binding to their surfaces, reducing the likelihood of depolymerization.
  • Microtubule-Associated Proteins (MAPs): Proteins such as tau, MAP2, and MAP4 play key roles in stabilizing microtubules. By binding along the microtubule lattice, they reduce the chances of depolymerization and help organize the microtubules into stable structures that are crucial for specialized functions like axon formation in neurons.
  • Post-Translational Modifications: Tubulin subunits can also undergo post-translational modifications such as acetylation, detyrosination, and polyglutamylation. These modifications can enhance the stability of microtubules or alter their interactions with other cellular proteins.

The overall balance between nucleation, elongation, and stabilization allows microtubules to grow and form complex intracellular networks that perform a wide range of functions, from cargo transport to cell division.

Disassembly (Depolymerization) of Microtubules

Microtubule disassembly is a rapid process that allows cells to reorganize their cytoskeleton, especially during events such as mitosis, cell migration, or in response to stress. This process involves the loss of tubulin dimers from the microtubule ends and is initiated when the stabilizing GTP cap is lost.

1. Catastrophe

The process of microtubule disassembly often begins with a phase known as catastrophe, where the microtubule transitions from a state of growth to rapid shrinkage. This happens when the GTP cap at the plus end is lost, exposing less stable, GDP-bound tubulin.
  • GTP Hydrolysis: As tubulin dimers are incorporated into the growing microtubule, the GTP bound to the β-tubulin subunit is hydrolyzed to GDP. The presence of GDP-bound tubulin destabilizes the microtubule because GDP-bound tubulin has a lower affinity for neighboring dimers. Once the GTP cap is lost, the microtubule becomes highly susceptible to depolymerization.
  • Rapid Shrinkage: During catastrophe, microtubules undergo rapid disassembly, losing tubulin dimers from the plus end. The rate of shrinkage can be much faster than the rate of growth, allowing the microtubule to be quickly dismantled when necessary, such as during mitotic spindle breakdown after cell division.

2. Rescue

Following a catastrophe, microtubules can sometimes switch back to a growing phase, a process known as rescue. Rescue occurs when GTP-bound tubulin dimers are reincorporated into the microtubule, re-establishing the GTP cap and halting further disassembly.
  • Stabilizing Proteins: Proteins such as Xenopus microtubule-associated protein 215 (XMAP215) help promote microtubule rescue by enhancing the addition of GTP-tubulin to the shrinking microtubule. This regulation ensures that microtubules can recover from disassembly and return to their functional roles.
  • Dynamic Instability: The alternating phases of growth, catastrophe, and rescue are characteristic of dynamic instability, a hallmark of microtubule behavior. This property enables microtubules to explore the intracellular space rapidly and adapt to changing cellular needs.

3. Severing

Microtubules can also be disassembled through severing, where specialized proteins break the microtubule into smaller fragments. This process creates new plus and minus ends, both of which can either grow or shrink depending on cellular conditions and the availability of free tubulin dimers.
  • Katanin and Spastin: Two major microtubule-severing proteins are katanin and spastin. These proteins cut through microtubules by destabilizing the interactions between tubulin dimers in the microtubule lattice. Severing is an important regulatory mechanism that allows cells to rapidly remodel their microtubule network during processes such as mitosis, neuronal growth, or cellular stress responses.
  • Fragmentation and Redistribution: Severing generates new microtubule fragments that can either disassemble completely or serve as new seeds for polymerization. In neurons, for example, severing by spastin plays a critical role in branching by allowing new microtubule segments to form and extend into different regions of the cell.



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SAQ

1 Fill in the blanks: 
a) The basic unit of microtubules is …………………

b) α tubulin occurs at.............end, and β tubulin is at ..............of microtubules

c) GTP-GTP tubulin cap stabilises and promotes the .......................

d) The plus end-directed motor protein of microtubules is ………….

e) The hydrolysis of GTP from β-tubulin causes …………. of microtubules.

f) The cellular function of γ-tubulins is. …………………….

g) Colchicine binds to ……………

Answers:
a) α β tubulin heterodimers
b) plus, minus
c) polymerisation of microtubules
d) kinesin
e) Depolymerisation 
f) nucleate the growth of MTs 
g) free tubulin

SAQ 2

SAQ 3 

TERMINAL QUESTIONS

6. Draw the labelled diagram of microtubules.




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