Microtubules

Microtubules make up one of three major parts of the cytoskeleton (Figure 1). Similar to other cytoskeletal filaments, they play a major role in structural organization and cell shape, but they are also important in a number of other cellular processes, such as cell division, cell motility and intracellular transport. Microtubules form a polar network of filaments that extends from the centrosome towards the plasma membrane. This organization is highly conserved in evolution, reflected in a striking similarity of microtubules across almost all species (Janke C. (2014)).

In the Cell Atlas, 463 genes (2% of all protein-coding human genes) have been shown to encode proteins that localize to the microtubule cytoskeleton and its substructures, including microtubule ends, cytokinetic bridge, midbody, midbody ring, and mitotic spindle (Figure 2 and 3). Functional enrichment analysis of the genes encoding microtubule-localizing proteins shows highly enriched GO-terms for biological processes related to cytoskeleton organization, cytoskeletal transport, cell division, and post-translational protein folding. More than half of the proteins detected at microtubules also localize to other cellular compartments, most commonly to the nucleoplasm, the cytosol and/or vesicles.


TUBA3D - A-431

TUBA3D - U-251 MG

TUBA3D - U-2 OS


DTNBP1 - U-2 OS

AURKB - U-2 OS

CAMSAP2 - U-2 OS

Figure 1. Examples of proteins localized to the microtubules and its substructures. TUBA1A is the major component of the microtubules, here shown to localize to the microtubules in three different cell lines (detected in A-431, U-251 and U-2 OS cells). DTNBP1 is a component of the BLOC-1 protein complex required for biogenesis of lysosome-related organelles. This protein was previously not known to localize to microtubules. By using independent antibodies DTNBP1 is shown to localize to microtubules (detected in U2-OS cells). AURKB is a key regulator of mitosis by being part of the chromosomal passenger complex that ensures the correct orientation of the chromosomes during their segregation. AURKB is localized to the cytokinetic bridge (detected in U2-OS cells). CAMSAP2 is a microtubule minus end protein that is expected to be involved in the nucleation and polymerization of microtubules. This protein is localized to the microtubule ends (detected in U2-OS cells).

  • 2% (463 proteins) of all human proteins have been experimentally detected in the microtubules by the Human Protein Atlas.
  • 104 proteins in the microtubules are supported by experimental evidence and out of these 17 proteins are enhanced by the Human Protein Atlas.
  • 357 proteins in the microtubules have multiple locations.
  • 265 proteins in the microtubules show a cell to cell variation. Of these 264 show a variation in intensity and 1 a spatial variation.

  • Proteins localizing to microtubules are mainly involved in organization of the cytoskeleton, cytoskeletal transport, protein folding and cell division.

Figure 2. 2% of all human protein-coding genes encode proteins localized to microtubules. Each bar is clickable and gives a search result of proteins that belong to the selected category.

The structure of microtubules

Substructures

  • Microtubules: 260
  • Microtubule ends: 6
  • Cytokinetic bridge: 154
  • Midbody: 56
  • Midbody ring: 28
  • Mitotic spindle: 88

Microtubules are physically robust polymers made up of α/β-tubulin heterodimers (Goodson HV et al. (2018); Wade RH. (2009)). The dimers first assemble into linear protofilaments. Subsequent lateral association of 13 protofilaments gives rise to a hollow tube, with an outer diameter of around 25 nm. Microtubules can grow very long and highly dynamic, with an ability to rapidly polymerize or depolymerize from the ends. The uniform orientation of the subunits results in a polar structure, with one fast-growing plus-end of exposed β-subunits and one slow-growing minus-end of exposed α-subunits. The cellular organization of microtubules varies between cell types, but in most cells, the minus ends of microtubules are anchored to the centrosomes near the nucleus while the plus ends radiate towards the periphery of the cell. The dynamic instability of microtubules is vital for the cell's ability to adapt its structural arrangements in response to different environmental conditions, and for mechanical processes (Desai A et al. (1997); Conde C et al. (2009)).


APC2 - U-2 OS

KIF18A

FAM83D

Figure 3. Examples of the substructures of the microtubules. Midbody ring: APC2 is localized to the midbody ring (detected in U-2 OS cells). Cytokinetic bridge: KIF18A is a motor protein of the kinesin family that regulates chromosome aggregation and suppresses centromere movements prior to anaphase, thus contributing to chromosome stability (detected in U-2 OS cells). Mitotic spindle: FAM83D is localized to the mitotic spindle (detected in A-431 cells).

The dynamics of microtubules are regulated by a group of microtubule-associated proteins (MAPs). In addition, microtubules are subjected to a number of different post-translational modifications that influence the structure in order to meet the requirements for their different functions, for example acetylation of lysine residues, detyrosination, glycosylation and glutamylation (Janke C. (2014); Wloga D et al. (2010)[Janke C, 2014]). A selection of proteins suitable to be used as markers for microtubules and the substructures are listed in Table 1. Highly expressed genes encoding proteins that localize to microtubules are listed in Table 2.

Table 1. Selection of proteins suitable as markers for the microtubules structure or its substructures.

Gene Description Substructure
TUBA1A Tubulin alpha 1a Microtubules
DTNBP1 Dystrobrevin binding protein 1 Microtubules
Midbody
CAMSAP2 Calmodulin regulated spectrin associated protein family member 2 Cytosol
Microtubule ends

Table 2. Highly expressed microtubules proteins across different cell lines.

Gene Description Average NX
TUBA1B Tubulin alpha 1b 130
BIRC5 Baculoviral IAP repeat containing 5 22
TUBA1A Tubulin alpha 1a 22
VPS4A Vacuolar protein sorting 4 homolog A 15
TUBA4A Tubulin alpha 4a 12
SKA1 Spindle and kinetochore associated complex subunit 1 8
FBXL20 F-box and leucine rich repeat protein 20 5
GAN Gigaxonin 3
TUBA8 Tubulin alpha 8 2
TUBA3D Tubulin alpha 3d 1

See the morphology of microtubules in human induced stem cells in the Allen Cell Explorer.

The function of microtubules

Similar to other cytoskeletal networks, a major function of the microtubule cytoskeleton is to supply mechanical strength to the cytoplasm and maintain the organization of organelles and other cellular compartments (Goodson HV et al. (2018)). As components of cilia and flagella, microtubules are also vital for cell migration and motility. These appendages are used in certain human cell types for cellular motility or extracellular transport of fluids, but cilia can also function as sensory organelles. Moreover, microtubules enable intracellular transport of organelles, vesicles and proteins with the help of ATP-driven motor proteins, making them key contributors to the secretory pathway (Schmoranzer J et al. (2003)). Motor proteins and microtubule dynamics are also employed to generate forces and movements. The two largest families of motor proteins are the dyneins and kinesins, which are moving in direction towards the minus and the plus end of microtubules, respectively.

Another highly important and well studied function of microtubules is in cell division through mitosis. Microtubules constitute a major part of the mitotic spindle (see Figure 3), which mediates segregation of sister chromatids to opposite poles. Spindle formation is an intricate process that involves both polymerization and depolymerization of microtubules, as well as movements generated by motor proteins. Sister chromatid separation is followed by cytokinesis, upon which microtubules of the central spindle are rearranged and compacted between the daughter cells, forming a cytokinetic bridge with a dense central structure called the midbody, which is eventually cleaved (see Figure 3) (Skop AR et al. (2004)).

Several diseases are linked to defective cellular transport due to abnormalities in microtubules. Hereditary diseases associated with defects in cilia, known as ciliopathies, and several neurodegenerative disorders, such as Parkinson's syndrome, are two such diseases (Waters AM et al. (2011); Matamoros AJ et al. (2016)). Moreover, as tumour growth is highly dependent on mitosis, there are many efficient anti-cancer drugs that target microtubules (Jordan MA et al. (2004)).

Gene Ontology (GO)-based analysis of genes encoding proteins localizing to microtubules in the Cell Atlas shows enrichment of functions and processes well in line with existing literature. The most highly enriched terms for the GO domain Biological Process are related to microtubule-based processes such as cytoskeleton organization, cilium morphogenesis and cell division (Figure 4a). Enrichment analysis of the GO domain Molecular Function shows enrichment of terms related to motor activity and tubulin binding (Figure 4b).

Figure 4a. Gene Ontology-based enrichment analysis for the microtubules proteome showing the significantly enriched terms for the GO domain Biological Process. Each bar is clickable and gives a search result of proteins that belong to the selected category.

Figure 4b. Gene Ontology-based enrichment analysis for the microtubules proteome showing the significantly enriched terms for the GO domain Molecular Function. Each bar is clickable and gives a search result of proteins that belong to the selected category.

Microtubules proteins with multiple locations

Approximately 77% (n=357) of the microtubule-localizing proteins in the Cell Atlas also localize to other compartments in the cell (Figure 5). The network plot shows that the most common locations shared with microtubules are the nucleoplasm, the cytosol and vesicles. Proteins with dual localization to microtubules and vesicles are overrepresented, likely reflecting the important role of microtubules as a transport system in the cell.

Figure 5. Interactive network plot of microtubule proteins with multiple localizations. The numbers in the connecting nodes show the proteins that are localized to the microtubules and to one or more additional locations. Only connecting nodes containing more than one protein and at least 0.5% of proteins in the microtubule proteome are shown. The circle sizes are related to the number of proteins. The cyan colored nodes show combinations that are significantly overrepresented, while magenta colored nodes show combinations that are significantly underrepresented as compared to the probability of observing that combination based on the frequency of each annotation and a hypergeometric test (p<=0.05). Each node is clickable and results in a list of all proteins that are found in the connected organelles.

Expression levels of microtubules proteins in tissue

Transcriptome analysis and classification of genes into tissue distribution categories (Figure 6) shows that genes encoding microtubule-localizing proteins are less likely to be detected in all tissues, but more likely to be detected in many tissues, compared to all genes presented in the Cell Atlas. There is also a slight overrepresentation of genes that are expressed in a single tissue. This points towards a somewhat more restricted pattern and tissue expression of genes encoding proteins that localize to microtubules.

Figure 6. Bar plot showing the percentage of genes in different tissue distribution categories microtubule-associated protein-coding genes compared to all genes in the Cell Atlas. Asterisk marks a statistically significant deviation (p≤0.05) in the number of genes in a category based on a binomial statistical test. Each bar is clickable and gives a search result of proteins that belong to the selected category.

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