What is Tubulin?

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In molecular biology, the term tubulin can refer to the protein superfamily or a specific protein within that family.

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The tubulin family of proteins are vital components of the eukaryotic cytoskeleton and are the main constituent of microtubules in living cells.

The tubulin proteins α- and β polymerize into long chains or filaments that form microtubules, an essential element of the eukaryotic cytoskeleton. These microtubules play a crucial role in cell support and cell movement, making tubulin imperative to normal cell function.

As well as serving an essential role in the structure and basic operation of cells, tubulin has also been identified as a potential novel therapeutic approach for cancer treatment.

Microtubules

Structural support, intracellular support, and DNA segregation are provided to eukaryotic cells by α- and β-tubulin, polymerized into microtubules. These structures are formed of rigid hollow, fibrous shafts of the globular protein, tubulin, that measure around 25 nm in diameter. The α- and β tubulins are encoded by small families of related genes and combine to form a dimer that the microtubules are constructed from.

Along with actin, microtubules are an essential component of the cytoskeleton, and they serve to determine a cell’s shape as well as its movements. Microtubules are vital to processes such as cell locomotion, separating chromosomes during mitosis, and the intracellular transportation of organelles. They also make up the internal structure of cilia and flagella.

Cell support

One major function of the microtubules that are built by tubulin is that they form the cytoskeleton of eukaryotic cells together with microfilaments and intermediate filaments. They are part of a team of components that provide the structure, shape, and internal organization of a cell. The specific structural role of microtubules is that they help the cell resist compression forces, and therefore enable it to maintain its intended shape and structure.

Cell movement

Through being a fundamental component of the cell’s cytoskeleton, tubulin is also crucial to the cell’s interaction with other organelles, and its movement. The cytoskeleton connects to every part of the cell membrane and every organelle. Tubulin and other filaments are known to be responsible for the movement of the cell membrane, organelles, and cytoplasm.

Types of tubulin

There are six known proteins that make up the tubulin superfamily in eukaryotes, however, not all six are consistently present across eukaryote species. In addition, many prokaryotic proteins have been identified as being related to tubulin. For a long time tubulin was considered specific to eukaryotes, but recent developments have proved this to be untrue.

In humans, there are five subgroups of tubulin: α-Tubulin, β-Tubulin, γ-Tubulin, δ and ε-Tubulin, and ζ-Tubulin. β-Tubulin is of particular interest because it forms a type of microtubule that is expressed exclusively in neurons.

Also, all drugs that bind to human tubulin also bind to β-tubulin, making it of interest as a therapeutic target. On the other hand, γ-Tubulin is known to be responsible for the nucleation and polar orientation of microtubules.

The proteins that have been identified in prokaryotes include BtubA/B, FtsZ, TubZ, and CetZ.

Applications in cancer treatment

There is a mounting body of research to support tubulin’s role in the development of new therapeutic drugs, particularly for anticancer drugs. Currently, a number of anticancer drugs are in existence that target tubulins, such as vinblastine, vincristine, and paclitaxel.

The anti-gout agent colchicine has also been found to impact on tubulin, binding to the protein and inhibiting microtubule formation, having the impact of decreasing inflammation. This drug has been linked with a decreased risk of prostate and colorectal cancers.

Further to this, there is evidence to show that griseofulvin, an anti-fungal drug, targets microtubule formation and is associated with the inhibition of proliferation of various types of cancer cells and inhibition of tumor growth.

Current research is looking further into how new anticancer therapies can be developed by targeting tubulins and the microtubules that they create.

They are of particular interest because they are known to be related to the dynamics of the mitotic spindle, which is associated with mitotic arrest and cell death. This is different to most other chemotherapeutic cancer drugs that act on DNA.

At this point, more research into tubulin and microtubules and their role in cancer is required to access the full potential they pose to the development of novel therapeutic approaches for the treatment of cancer.

A focus of these future developments will likely be on minimizing the adverse side effects that are related with the use of tubulin targeted drugs, such as stomatitis, nausea, vomiting, diarrhea, constipation, paralytic ileus, urinary retention, bone marrow suppression, musculoskeletal effects, severe weakness, hypotension, alopecia, and more.

There are also a number of limitations of this kind of drug therapy that continued research is likely to focus on overcoming. Future work will hope to improve antitumor activity, toxicity profile, and drug formulation.

Sources:

Cooper, G. (2019). Microtubules. [online] Ncbi.nlm.nih.gov. Available at: https://www.ncbi.nlm.nih.gov/books/NBK9932/ [Accessed 23 Nov. 2019].
D. Katsetos, C. and Draber, P. (2012). Tubulins as Therapeutic Targets in Cancer: from Bench to Bedside. Current Pharmaceutical Design, 18(19), pp.2778-2792. https://www.ncbi.nlm.nih.gov/pubmed/22390762
Hammond, J., Cai, D. and Verhey, K. (2008). Tubulin modifications and their cellular functions. Current Opinion in Cell Biology, 20(1), pp.71-76. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2274889/
Parker, A., Kavallaris, M. and McCarroll, J. (2014). Microtubules and Their Role in Cellular Stress in Cancer. Frontiers in Oncology, 4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4061531/

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Related questions

01Can you provide an overview of your experience and background in research and drug discovery, including any specific areas of expertise or research interests?

My lab primarily focuses on neuroscience, but we approach problems from the perspective of axon biology. We're deeply interested in how neurons develop, undergo polarization and establish/maintain connectivity. This understanding helps not only in the development of the nervous system but also sheds light on age-related degeneration linked to the loss of axon connectivity. We use various cellular models, such as compartmentalised microfluidic neuronal cultures, to study how axons face different environments compared to cell bodies. Within this context, our research is focused on RNA biology, specifically the role of non-coding RNAs or microRNAs in regulating local axon protein synthesis. This knowledge is especially valuable when exploring different diseases and conditions like pain or neurodegeneration.

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02How does Protein A affect humans?

S. aureus is a Gram-positive and cocci-shaped bacterium, meaning that it appears purple with ‘Gram stain’, and these bacterial are seen as clusters of small, spherical cells. S. aureus is a part of the human microbiome – mostly being found on the surface of the skin and all mucous membranes (e.g. eyes, mouth and ears). They are opportunistic bacteria, meaning that if a break in the skin occurs, or if the host becomes immunodeficient in some way, S. aureus can eventually cause an infection. When S. aureus does infect a human host, it may result in a variety of different diseases, but very commonly it causes recurrent soft tissue and skin infections. These infections have become more prevalent in recent years, mainly as nosocomial forms, as methicillin-resistant strains of S. aureus (MRSA) have evolved in hospitals across the western world. In humans, protein A (once it is released into the extra-cellular environment) can bind with the ‘Fc’ fragment of immunoglobulin G (IgG) and has been observed to be antiphagocytic in vitro - which is consistent with its IgG binding abilities, as binding to IgG can interfere with bacterial attachment by the antibody. This means that it can prevent itself from being destroyed by certain elements of the human immune system (as was also similarly observed in the guinea pig experiment from 2013). S. aureus infections, such as endocarditis, are usually treated with a strong course of antibiotics. Protein A can therefore function slightly differently in different species, but always has the same goal: it interferes with the host’s B-cells within their immune system to prevent S. aureus from being phagocytosed and destroyed. This is an ideal adaptation, and when coupled with the known propensity of S. aureus to be more easily transmitted than other coagulase-positive bacteria, it indicates faster and more widespread bacterial transmission.

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03What roles does the system play?

The endogenous opioids and their receptors are widely distributed throughout the central and peripheral nervous systems, particularly the parts of these systems that regulate pain, emotion, reward, stress responses, motivation, drug addiction, and autonomic control. The differential expression and location of the various receptor subtypes across different neurons account for the wide range of opioid-related behaviors. The activation of µ-opioid receptors is mainly known for playing a role in pain relief. Still, research has also indicated it may be involved in behaviors related to survival, such as appetite and reproduction. The activity of µ-opioid receptors is also known to play a critical role in responses to social stimuli by modulating responses to social rejection or social acceptance, for example. Activation of the δ-opioid receptors and κ-opioid receptors is also known to be involved in pain modulation. Also, studies have shown that NOP activation is involved in pain mechanisms and several behaviors related to psychological stress. Alterations in the endogenous opioid system are suspected to be involved in Parkinson's disease, seizures, neuroprotective mechanisms, and depression.

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04Are there more complex motifs?

These α-helices and β-sheets are not only joined by loops and β-turns but can also be joined by a β-sheet or an α-helix. Metal ions can also play a role in the formation of motifs.

Source: www.news-medical.net ↗

05What do leucine and isoleucine do in the human body?

Leucine and isoleucine are transported into organs (including the brain) by the use of L1-neutral amino acid transporter, or LAT1. As other amino acids are also transported by LAT1, leucine and isoleucine must compete for a binding site. Amino acids imported into the brain can be used to synthesize neurotransmitters, therefore changes in amino acid concentrations may have an effect on the neurotransmitters that are made. Leucine has additional roles; it may inhibit breakdown of muscle, causes the secretion of insulin from pancreatic β-cells, as well as modulate food intake regulation through its action on the central nervous system.

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Peptide Therapy Guide Editorial Team

Editorial team for Peptide Therapy Guide.

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Microtubules

Cell support

Cell movement

Types of tubulin

Applications in cancer treatment

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