Chapter 16: Cytoskeleton

Cytoskeleton

• The cytoskeleton is a dynamic network of protein filaments found within the cytoplasm of cells.

Function of the Cytoskeleton:

• Structural Support: The cytoskeleton provides structural support to the cell, giving it shape, strength, and stability.
• Cell Motility: The cytoskeleton enables cellular movement by providing tracks for the transport of organelles, vesicles, and other cellular components.
• Cell Division: The cytoskeleton plays a critical role in cell division by forming the mitotic spindle and facilitating chromosome segregation.
• Intracellular Transport: It aids in the transport of materials within the cell, allowing for the movement of organelles and vesicles along cytoskeletal tracks.
• Cell Adhesion: The cytoskeleton is involved in cell adhesion processes, including the formation of cell-cell junctions and anchoring cells to the extracellular matrix.
• Cell Signaling: It participates in cell signaling by organizing and positioning signaling molecules and receptors within the cell.
• Mechanical Sensing: The cytoskeleton allows cells to sense and respond to mechanical forces and external stimuli.

Origin of the Cytoskeleton:

• Prokaryotic Origin: The cytoskeleton-like structures are not exclusive to eukaryotic cells. Prokaryotes also possess cytoskeletal elements, albeit simpler and less diverse.
• Evolutionary Conserved: The cytoskeleton is evolutionarily conserved, indicating its ancient origins and importance in cellular function.
• Intermediate Filaments: The earliest cytoskeletal structures in eukaryotes were likely the intermediate filaments, providing mechanical support and stability.
• Actin Filaments: Actin filaments evolved later and are found in eukaryotes, providing cellular motility, shape changes, and intracellular transport.
• Microtubules: Microtubules, composed of tubulin proteins, are believed to have emerged later in evolution and are involved in cell division, intracellular transport, and cell shape.
• Molecular Motors: Molecular motors, such as myosin, kinesin, and dynein, evolved to interact with the cytoskeleton and enable movement and transport within the cell.
• Crosslinking Proteins: Crosslinking proteins, including spectrin and filamin, evolved to strengthen and stabilize the cytoskeletal network.

Actin and Actin-Binding proteins

Actin:

• Actin is a highly conserved protein that forms filaments in eukaryotic cells.
• It is a major component of the cytoskeleton and plays a crucial role in cell structure and movement.
• Actin filaments are polarized, with a fast-growing plus end and a slow-growing minus end.
• There are three main isoforms of actin: alpha, beta, and gamma, which are expressed in different tissues and have distinct functions.
• Actin monomers can assemble into long filaments, forming a dynamic network throughout the cell.
• The assembly and disassembly of actin filaments are tightly regulated by a variety of actin-binding proteins.

Actin-binding proteins:

• Actin-binding proteins are a diverse group of proteins that interact with actin filaments, modulating their assembly, organization, and function.
• Actin-binding proteins can be classified into several categories based on their binding sites and functions.
• Nucleating proteins, such as Arp2/3 complex and formins, promote the formation of new actin filaments.
• Capping proteins, like CapZ and tropomodulin, bind to the ends of actin filaments, regulating their polymerization and depolymerization.
• Severing proteins, such as cofilin and gelsolin, break actin filaments into shorter segments, enhancing their turnover.
• Bundling proteins, including alpha-actinin and fimbrin, cross-link actin filaments, promoting the formation of bundled structures.
• Motor proteins, like myosins, generate force by interacting with actin filaments and participating in cell motility and muscle contraction.
• Actin-binding proteins also participate in other cellular processes, such as endocytosis, cell adhesion, and intracellular signaling.

Overall, actin and actin-binding proteins form a complex network that regulates cell shape, movement, and a multitude of other cellular processes. Their tight coordination ensures proper cell function and dynamics, highlighting the significance of actin and actin-binding proteins in cell biology.

Myosin and Actin

Myosin:

• Myosin is a family of motor proteins found in eukaryotic cells that interact with actin filaments.
• It is best known for its role in muscle contraction, but myosins are also involved in a wide range of cellular processes.
• Myosin molecules consist of two main components: a globular head domain and a tail domain.
• The head domain contains an ATPase activity that allows myosin to hydrolyze ATP and convert chemical energy into mechanical work.
• Myosin molecules are classified into different types, with each type having specific functions and localization within cells.
• In muscle cells, myosin II forms thick filaments that interact with actin filaments during contraction.
• Myosin V and myosin VI are involved in intracellular transport, carrying cargo along actin filaments in a directional manner.
• Myosin I and myosin IX are implicated in membrane dynamics and cell signaling processes.
• Myosin motors move along actin filaments in a stepwise manner, using ATP hydrolysis to generate force and propel cellular components.
• The movement of myosin along actin filaments is regulated by calcium ions, phosphorylation, and other regulatory proteins.

The interaction between myosin and actin:

• Myosin interacts with actin filaments through the globular head domain, which binds to actin and undergoes conformational changes upon ATP hydrolysis.
• The binding and release of ATP by myosin trigger the movement of myosin along actin filaments, a process known as the cross-bridge cycle.
• The movement of myosin along actin generates force and allows for cellular processes like muscle contraction and intracellular transport.
• The binding of myosin to actin is regulated by calcium ions, regulatory proteins, and signaling pathways.
• The coordination between myosin motors, actin filaments, and regulatory proteins ensures the proper functioning of cellular processes that rely on myosin-actin interactions.

Microtubules

• Microtubules are hollow cylindrical structures composed of protein subunits called tubulins.
  • They are a key component of the cytoskeleton, providing structural support and facilitating various cellular processes.
• Microtubules are involved in cell division, intracellular transport, cell motility, and the maintenance of cell shape.
• The tubulin subunits that make up microtubules consist of α-tubulin and β-tubulin, which form a dimer.
• The dimers polymerize longitudinally to create protofilaments, and multiple protofilaments align side by side to form a microtubule.
• Microtubules have polarity, with a fast-growing plus end and a slow-growing minus end.
• They can undergo dynamic instability, switching between periods of growth (polymerization) and shrinkage (depolymerization).
• Microtubule dynamics are regulated by various factors, including microtubule-associated proteins (MAPs) and motor proteins.
  • Microtubule-associated proteins (MAPs) stabilize microtubules, regulate their assembly and disassembly, and facilitate interactions with other cellular components.
• Motor proteins, such as kinesins and dyneins, move along microtubules, enabling intracellular transport and cell motility.
• Microtubules play a critical role in cell division by forming the mitotic spindle, which segregates chromosomes during mitosis and meiosis.
  • They are also involved in the organization of cilia and flagella, which are important for cellular locomotion and sensory functions.
• Microtubules provide tracks for intracellular transport, allowing vesicles, organelles, and macromolecules to move within the cell.
• The stability and organization of microtubules are regulated by post-translational modifications, including acetylation, phosphorylation, and polyglutamylation.
• Microtubule-based drugs, such as taxanes and vinca alkaloids, are used in cancer chemotherapy due to their ability to disrupt cell division.

Intermediate Filaments and Septins

Intermediate Filaments:

• Intermediate filaments (IFs) are a class of cytoskeletal proteins that provide structural support and mechanical strength to cells.
  • Unlike microtubules and actin filaments, intermediate filaments exhibit greater stability and are less dynamic.
• Intermediate filaments are composed of a diverse family of proteins, including keratins, vimentin, desmin, lamins, and neurofilaments, among others.
• The specific type of intermediate filament expressed in a cell depends on its tissue type and function.
• Intermediate filaments are characterized by a common structural motif consisting of a central alpha-helical rod domain flanked by non-helical head and tail domains.
  • The rod domains of two intermediate filament proteins form a coiled-coil dimer, which then associates with other dimers to form a stable tetrameric structure.
• The assembly of intermediate filaments into higher-order structures provides mechanical integrity to cells and tissues.
• Intermediate filaments play important roles in maintaining cell shape, providing resistance to mechanical stress, and anchoring organelles.
• They are particularly abundant in epithelial cells, muscle cells, and nerve cells.
• Mutations in intermediate filament proteins can lead to various genetic disorders, such as epidermolysis bullosa, muscular dystrophies, and neurodegenerative diseases.

Septins:

• Septins are a family of GTP-binding proteins that form filamentous structures and are involved in diverse cellular processes.
• They were originally identified in yeast as proteins that play a role in cell division, but their functions have since been expanded to various other processes.
• Septins can assemble into higher-order structures, including filaments, rings, and gauze-like networks.
  • Septin filaments can associate with membranes, actin filaments, and microtubules, contributing to their organization and function.
  • Septins are involved in cytokinesis, where they form a contractile ring at the site of cell division, aiding in the formation of the cleavage furrow.
• They also participate in cell migration, vesicle trafficking, exocytosis, cell polarity, and membrane remodeling.
• Dysregulation of septin proteins has been linked to several diseases, including cancer, neurodegenerative disorders, and infections.
• Septins interact with various other proteins, including actin-binding proteins, motor proteins, and membrane-associated proteins, to carry out their functions.
• Post-translational modifications, such as phosphorylation and sumoylation, regulate the assembly and disassembly of septin structures.

Cell Polarization and Migration

Cell Polarization:

• Cell polarization refers to the asymmetric distribution of cellular components, such as proteins, organelles, and cytoskeletal elements, within a cell.
• It is a fundamental process in cell biology and is essential for many cellular functions, including cell migration.
• Cell polarization is driven by intracellular signaling pathways and external cues from the cell's microenvironment.
• The establishment of cell polarity involves the organization and localization of key protein complexes, including polarity regulators and cytoskeletal elements.
• Polarity regulators, such as small GTPases (e.g., Rho, Rac, Cdc42), play a crucial role in coordinating cytoskeletal rearrangements and vesicle trafficking during cell polarization.
• The cytoskeleton, particularly actin filaments, is central to cell polarization. Actin filaments undergo dynamic rearrangements, leading to the formation of polarized structures like lamellipodia and filopodia.
• Microtubules and intermediate filaments also contribute to cell polarization, aiding in the organization of the cell's internal architecture.
• Cell polarization is often associated with the establishment of a leading edge and a trailing edge, which are crucial for cell migration.
• Protein complexes, such as the PAR complex and Scribble complex, localize to specific regions of the cell and regulate cell polarity by asymmetrically distributing signaling molecules and cytoskeletal components.
• Cell polarity is important for diverse cellular processes, including embryonic development, tissue morphogenesis, and directed cell migration.

Cell Migration:

• Cell migration refers to the movement of cells from one location to another within an organism.
• It is a dynamic process that is essential during embryonic development, immune responses, tissue repair, and cancer metastasis.
• Cell migration involves a series of coordinated steps, including polarization, protrusion, adhesion, traction, and rear release.
• Leading edge protrusions, such as lamellipodia and filopodia, extend in the direction of migration, sensing and responding to extracellular cues.
• Actin polymerization drives the formation of these protrusions, providing the force necessary for cell movement.
• Adhesion complexes, such as focal adhesions and hemidesmosomes, mediate cell-substrate interactions and provide traction for the cell to move forward.
• Integrins, a family of transmembrane receptors, play a crucial role in cell adhesion and signaling during migration.
• Rear release involves the detachment of the trailing edge and the coordination of cytoskeletal reorganization to facilitate cell movement.
• Various signaling pathways, including those involving small GTPases, tyrosine kinases, and chemokines, regulate cell migration by modulating actin dynamics, adhesion turnover, and cell polarity.
• Extracellular matrix (ECM) components, such as collagen and fibronectin, provide physical and chemical cues that guide cell migration.
• Cell migration is a complex process influenced by a multitude of factors, including cell-cell interactions, growth factors, mechanical forces, and gradients of chemical signals.

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