MICROFILAMENTS: CHARACTERISTICS, STRUCTURE, FUNCTIONS, PATHOLOGY - BIOLOGY - 2025

The microfilaments or actin filaments, are one of the three main components of the cytoskeleton of eukaryotic cells (microfilaments, microtubules and intermediate filaments) and are composed of small filaments of a protein called actin (actin polymers).

In eukaryotes, the genes that code for actin microfilaments are highly conserved in all organisms, which is why they are often used as molecular markers for studies of various kinds.

Photograph of the actin filaments of a cell stained (Source: Howard Vindin via Wikimedia Commons)

Microfilaments are distributed throughout the cytosol, but they are especially abundant in the region underlying the plasma membrane, where they form a complex network and associate with other special proteins to form the cytoskeleton.

The microfilament networks in the cytoplasm of mammalian cells are encoded by two of the six genes described for actin, which are involved in the dynamics of microfilaments and are even very important during the differentiation of stem cells.

Many authors agree that microfilaments are the most diverse, versatile, and important proteins in the cytoskeleton of most eukaryotic cells, and it is important to remember that these are not found in prokaryotic microorganisms.

In this type of cell, on the other hand, there are filaments that are homologous to microfilaments, but which are made up of another protein: the MreB protein.

At present, the gene encoding this protein is thought to be a possible ancestral gene for actin in eukaryotes. However, the sequence homology of the amino acids that make up the MreB protein is only 15% with respect to the actin sequence.

As they are a fundamental part of the cytoskeleton, any phenotypic defect in both microtubules and intermediate filaments and actin microfilaments (cytoskeleton) can cause different cellular and systemic pathologies.

Characteristics and structure

Microfilaments are made up of actin family protein monomers, which are highly abundant contractile proteins in eukaryotic cells, since they also participate in muscle contraction.

These filaments have a diameter between 5 and 7 nm, which is why they are also known as thin filaments and are made up of two forms of actin: the globular form (G actin) and the filamentous form (F actin).

The proteins that participate in the cytoskeleton are known as γ and β actins, while those that participate in contraction are usually α actins.

The proportion of globular actin and filamentous actin in the cytosol depends on the cellular needs, since microfilaments are highly variable and versatile structures, which are constantly growing and shortening by polymerization and depolymerization.

G actin is a small globular protein, made up of almost 400 amino acids and with a molecular weight of around 43 kDa.

The G-actin monomers that make up the microfilaments are arranged in the form of a helical strand, since each undergoes a twist when associated with the next.

G actin associates with one molecule of Ca2 + and another of ATP, which stabilize its globular form; while F actin is obtained after hydrolysis of the terminal phosphate of the ATP molecule into G actin, which contributes to polymerization.

Organization

Actin filaments can be organized into "bundles" or "networks" that have different functions within cells. The bundles form parallel structures linked by fairly rigid cross bridges.

Networks, on the other hand, are looser structures, like three-dimensional meshes with the properties of semi-solid gels.

There are many proteins that associate with actin filaments or microfilaments and are known as ABP (actin binding proteins), which have specific sites for it.

Many of these proteins allow microfilaments to interact with the other two components of the cytoskeleton: microtubules and intermediate filaments, as well as with the other components on the inner face of the plasma membrane.

Other proteins that microfilaments interact with include nuclear laminae and spectrin (in red blood cells).

How are actin filaments formed?

Since globular actin monomers always bind in the same way, oriented in the same direction, microfilaments have a defined polarity, with two ends: one "more" and one "less".

The polarity of these filaments is very important, since they grow considerably faster at their positive end, where the new G-actin monomers are added.

Graphic representation of actin microfilament formation (Source: derivative work: Retama (talk) Thin_filament_formation.svg: Mikael Häggström via Wikimedia Commons)

The first thing that takes place during the polymerization of actin filaments is a process known as "nucleation", which consists of the association of three monomers of the protein.

New monomers are added to this trimer at both ends, so that the filament grows. G-actin monomers are capable of hydrolyzing ATP with each binding, which has implications on the rate of polymerization, since actin-ATP moieties dissociate with greater difficulty than actin-ADP moieties.

ATP is not necessary for polymerization and the specific role of its hydrolysis has not yet been elucidated.

Some authors consider that, since actin polymerization events are rapidly reversible, the ATP associated with these processes can represent up to 40% of the total cellular turnover of this energetic molecule.

Regulation

Both the polymerization of actin filaments and their depolymerization are processes highly regulated by a series of specific proteins, which are responsible for the remodeling of the filaments.

Examples of the proteins that regulate depolymerization are the actin depolymerization factor cofilin. Another protein, profilin, has an opposite function, since it stimulates the association of monomers (by stimulating the exchange of ADP for ATP).

Features

Microfilaments interact with myosin filaments that are associated with transmembrane proteins that have a domain in the cytosol and another in the cell exterior, thus participating in the processes of cell mobility.

These microfilaments associated with the plasma membrane mediate various cellular responses to different classes of stimuli. For example, cell adhesion in epithelial tissues is driven by transmembrane proteins known as cadherins, which interact with microfilaments to recruit response factors.

Actin filaments interact with intermediate filaments to cause extracellular stimuli to be transmitted to key sites such as ribosomes and chromosomes within the nucleus.

Representation of the intracellular motor function of actin microfilaments (Source: Boumphreyfr via Wikimedia Commons)

A classic and much studied function of microfilaments is their ability to form "bridges", "rails" or "highways" for the movement of the motor protein myosin I, which is capable of loading transport vesicles from organelles to the membrane. plasma in the secretory pathways.

Microfilaments also interact with myosin II to establish the contractile ring that forms during cytokinesis, precisely during the last stage of cell division in which the cytosol is separated from stem and daughter cells.

In general, F-actin microfilaments modulate the distribution of some organelles such as the Golgi complex, endoplasmic reticulum, and mitochondria. Furthermore, they also participate in the spatial positioning of mRNAs so that they are read by ribosomes.

The entire cellular set of microfilaments, especially those that are closely related to the plasma membrane, participate in the formation of the undulating membranes of cells that have a constant active movement.

They are also involved in the formation of microvilli and other common bumps on the surface of many cells.

Example of functions in the liver

Microfilaments participate in the process of bile secretion in hepatocytes (liver cells) and also in peristaltic movements (coordinated contraction) of the hepatic canaliculi.

They contribute to the differentiation of plasma membrane domains thanks to their association with different cytosolic elements and the control they exert over the topography of these intracellular elements.

Related pathologies

There are few diseases associated with primary defects in the structure or with regulatory proteins and enzymes in the synthesis of microfilaments, despite the fact that these are directly involved in a large number of functions.

The low rate of diseases and malformations in the primary structure of microfilaments is due to the fact that, generally, there are multiple genes that encode both actin and its regulatory proteins, a phenomenon known as “genetic redundancy”.

One of the most studied pathologies is the vitrification of the oocytes on their cytoskeleton, where an interruption in the network of cortical microfilaments is observed, as well as a depolymerization and disorganization of the microtubules of the mitotic spindle.

In general terms, this vitrification causes a chromosomal dispersion, since it leads to a derangement in the compaction of all the chromatin.

The cells that have a greater organization and proportion of microfilaments in their cytoskeleton are the cells of the striated muscle, therefore, most of the pathologies are associated with a malfunction of the contractile apparatus.

Defective or atypical microfilaments have also been associated with the disease of the bones known as Paget's disease.

References

1. Aguilar-Cuenca, R., Llorente-González, C., Vicente, C., & Vicente-Manzanares, M. (2017). Microfilament-coordinated adhesion dynamics drives single cell migration and shapes whole tissues. F1000Research, 6.
2. Dos Remedios, CG, Chhabra, D., Kekic, M., Dedova, IV, Tsubakihara, M., Berry, DA, & Nosworthy, NJ (2003). Actin binding proteins: regulation of cytoskeletal microfilaments. Physiological Reviews, 83 (2), 433-473.
3. Guo, H., Fauci, L., Shelley, M., & Kanso, E. (2018). Bistability in the synchronization of actuated microfilaments. Journal of Fluid Mechanics, 836, 304-323.
4. Lanza, R., Langer, R., & Vacanti, JP (Eds.). (2011). Principles of tissue engineering. Academic press.
5. Robbins, J. (2017). Diseases of the Cytoskeleton: The Desminopathies. In Cardioskeletal Myopathies in Children and Young Adults (pp. 173-192). Academic Press.