Intermediate Filaments and Cytoskeleton

Cytoskeleton, Part 3

  • Discussion on muscular dystrophies resulting from mutations in intermediate filaments (IF).

    • Proposed mechanism connecting genetic mutations to observed phenotypes in muscular dystrophies.

Lesson Objectives

  • Aim for the session:

    • Describe the molecular structure of intermediate filaments (IF).

    • Summarize the functions of intermediate filaments.

    • Predict how changes to intermediate monomers affect structural integrity of IF.

Intermediate Filament Structure

  • Composition and Characteristics:

    • Intermediate filaments are made up of several different, albeit related, monomers.

      • Examples: Vimentins, Keratins, and Lamins; the name of the monomer often corresponds to the name of the polymer itself.

    • Dimers consist of parallel IF monomers that align to form antiparallel tetrads.

    • Tetrads further associate end-to-end to form protofibrils which create a four-coiled filament as illustrated in Figure 18-50 from MCB.

Properties of Intermediate Filaments

  • Unique features distinguishing IF from microfilaments and microtubules:

    • Lack of Polarity:

      • Unlike microfilaments and microtubules, intermediate filaments do not exhibit polarity, thus they do not function as tracks for motor proteins.

    • Tensile Strength and Stability:

      • Among the three cytoskeletal structures (intermediate filaments, microfilaments, microtubules), IF display the highest tensile strength and stability.

      • IF assembly and disassembly rates are slower, enhancing their suitability for structural support, adhesion, and protection (Janmey et al., 1991).

    • Energy Utilization:

      • IF protofibrils do not bind to nucleotides such as ATP or GTP. Instead, compression and stretching rely on sidechain interactions that naturally revert to a “resting” position without energy input (Vermeire et al., 2021).

Comparative Table on Cytoskeletal Elements

  • Fillable comparison table to assess key properties across Microfilaments, Microtubules, and Intermediate Filaments:

    • Categories: Monomers, Nucleotides, Polarity, Arrangement, Stability, Strength.

Type I & II Intermediate Filaments: Keratins

  • Description and Role:

    • Keratins are primarily found in epithelial cells, comprising one acidic monomer and one basic monomer which coil together to form dimers.

    • The electrostatic attraction between opposite charges of the monomers leads to robust interactions.

    • Functions primarily in permanent structures including hair, nails, and desmosomes.

    • Dysfunctions involving keratin-5 or keratin-14 can lead to conditions such as epidermolysis bullosa simplex (McLean & Irvine, 2007).

Type III Intermediate Filaments

  • Specific Proteins and Functions:

    • Include Desmin, Vimentin, Glial Fibrillary Acidic Protein (GFAP), among others, crucial for maintaining structural integrity in cells under substantial deformation (e.g., muscle cells, glial cells, fibroblasts).

    • Certain Type III IFs like GFAP play a role in injury responses; GFAP is instrumental in forming a glial scar after spinal cord injuries, providing stability to damaged tissues but hindering regeneration (Manrique-Castano & ElAli, 2021).

Neutrophils and Vimentin Role in Cell Structure

  • Investigation into neutrophils that have lobed nuclei:

    • Vimentin’s role in determining the lobularity of neutrophil nuclei:

      • It plays a minimal or no role by itself in lobulation, indicating interaction with other proteins is necessary to determine the precise number of lobes.

      • It is not solely responsible for the lobular structure in neutrophils.

Type IV Intermediate Filaments: Neurofilaments

  • Functional Role and Expression:

    • Neurofilaments are mainly involved in stabilizing cellular structures and linking them together.

    • Primarily expressed in nervous tissue, though some forms are present in muscle cells.

    • The detection of loose neurofilaments in cerebrospinal fluid (CSF) or blood is utilized as a biomarker for neural damage (Bomont, 2021).

Type V Intermediate Filaments: Lamins

  • General Information and Genetic Disorders:

    • Lamins are crucial components of the nuclear lamina and are expressed in nearly all cell types, with expression levels varying based on cellular requirements.

    • They are essential for forming the basal lamina (an extracellular matrix component) between the epithelium and endothelium.

    • Autosomal Dominant Leukodystrophy (ADLD), a rare genetic condition, results from Lamin B1 (LMNB1) overexpression.

    • The irregularly shaped nuclei observed can be indicative of a thickened nuclear envelope, affecting cellular function (as seen in microscopy panels).

Identification of Lamin Disorders

  • Some forms of epidermolysis bullosa result from lamin dysfunctions rather than keratin issues:

    • Microscopy can be utilized to differentiate these conditions by exploring the structural manifestations of lamin versus keratin abnormalities in epithelial tissue (Srinivasan et al., 2018).

Conclusion of Lesson Objectives

  • Reinforcement of aims:

    • Students should be able to articulate the molecular structure of intermediate filaments.

    • Summarize the various functions of intermediate filaments.

    • Predict the consequence of alterations to intermediate monomers on the structural integrity of these filaments.