Cytoskeleton 4

Introduction to the Cytoskeleton

  • The cytoskeleton is an essential cellular structure comprising various filaments that provide support and shape to cells.

  • It consists primarily of three families of protein filaments:

    • Actin filaments

    • Microtubules

    • Intermediate filaments

Intermediate Filaments

  • Characteristics:

    • Composed of stable polymers that provide structural support.

    • Require proteases for breakdown.

  • Gene Organization:

    • Intermediate filament genes are classified into six groups in humans (Classes I – VI).

    • For example, Class V consists of lamins, critical components of nuclear structure.

  • Posttranslational Modifications:

    • Undergo a range of modifications post-translationally, affecting their function and stability.

Structure of Intermediate Filaments

  • Monomers and Dimers:

    • Composed of a-helical regions that form coiled-coil dimers.

    • A staggered arrangement of two coiled-coil dimers forms a tetramer.

  • Filament Growth:

    • Lateral association of multiple tetramers creates filaments.

    • Addition of tetramers contributes to filament elongation.

Function and Distribution of Intermediate Filaments

  • Intermediate filaments are found in areas where mechanical strength is necessary.

  • Major Types of Intermediate Filament Proteins in Vertebrate Cells:

    • Nuclear Lamins (A, B, C): Located in the nuclear lamina (inner lining of the nuclear envelope).

    • Vimentin-like proteins: Present in many cells of mesenchymal origin.

    • Desmin: Found in muscle cells.

    • Glial Fibrillary Acidic Protein: Present in astrocytes and some Schwann cells.

    • Peripherin: Found in some neurons.

    • Type I and II Keratins: Located in epithelial cells and their derivatives (hair, nails).

    • Axonal Neurofilament Proteins (NF-L, NF-M, NF-H): Located in neurons.

Diseases Associated with Cytoskeletal Mutations

  • Mutations in cytoskeletal genes can lead to diseases; notable examples include Laminopathies.

  • Hutchinson-Gilford Progeria Syndrome:

    • Caused by recurrent de novo point mutations in the lamin A gene.

    • This condition leads to accelerated aging and associated symptoms.

Molecular Mechanism of Progeria

  • Common mutation involves a GGC to GGU change within the lamin A transcript.

  • Resulting protein changes include the creation of a new splice site in exon 11, altering the normal mRNA and leading to dysfunctional protein.

Summary of Key Concepts

  • The cytoskeleton is made of three structures: actin, microtubules, and intermediate filaments.

  • Cytoskeletal structures involve complex assembly into protofilaments before forming mature filaments.

  • Nucleotide binding (NTP/NDP) facilitates efficient depolymerization at the filament minus-end.

  • Key processes:

    • Treadmilling and dynamic instability influence filament dynamics.

    • Energy-dependent motors, such as myosin (actin) and kinesin & dynein (microtubules), facilitate movement along filaments.

  • The cytoskeleton's organization and functionality depend on the sites of nucleation and bundling of filaments.