Lecture 17

• Intermediate Filaments (IFs)

  A key component of the cytoskeleton, responsible for maintaining cell shape, integrity, and providing mechanical strength
• Intermediate Filaments

  • Unlike microtubules and actin filaments, IFs are primarily involved in withstanding mechanical stress rather than facilitating movement
• Core Structure of IF proteins

  Each IF protein has a central rod domain, which is a coiled-coil structure flanked by globular N- and C-terminal domains
• Assembly of Intermediate Filaments

  1. Two IF proteins dimerize in parallel

  2. Two dimers align in an antiparallel manner to form a staggered tetramer

  3. Tetramers associate end-to-end and laterally to form the mature filament
• Classes of Intermediate Filaments

  • Class I and II: Acidic and basic keratins, found in epithelial cells
  • Class III: Vimentin (in mesenchymal cells), desmin (in muscle cells), and peripherin (in peripheral neurons)
  • Class IV: Neurofilaments and alpha-internexin, located in nerve cells
  • Class V: Lamins, which form a meshwork underlying the inner nuclear membrane
• Mutations or dysfunctions in IF genes

  Can lead to various diseases, often by compromising the structural integrity of tissues
• Diseases linked to IF dysfunction

  • Epidermolysis Bullosa Simplex: Caused by mutations in keratin genes, leading to skin fragility and blistering
  • Alexander Disease: A rare neurological disorder linked to mutations in the gene for GFAP, an intermediate filament protein in astrocytes
• Desmosomes and Hemidesmosomes

  IFs connect to desmosomes (cell-cell adhesion) and hemidesmosomes (cell-ECM adhesion), providing tensile strength and distributing mechanical stress across the cell surface
• Experiments injecting labeled keratin into cells have demonstrated how newly synthesized IF proteins incorporate into pre-existing networks, reinforcing cell structure over time
• Studies where type I keratin was labeled and injected into epithelial cells showed that keratin initially forms aggregates before integrating into existing filaments, highlighting the dynamic nature of IF assembly and maintenance
• Role of IFs in tissue integrity

  In tissues like skin and gut epithelium, keratins provide mechanical strength to withstand shear and pressure forces, crucial for barrier functions and organ protection
• Role of IFs in body mechanics and movement

  IFs contribute to the overall mechanical properties of tissues involved in functions like food mastication, body movement, and blood circulation
• Keratin expression in skin layers

  • Basal Layer: Keratin 5 and Keratin 14 (K5/K14 heterodimers)
  • Spinous Layer: Keratin 1 and Keratin 10 (K1/K10 heterodimers)
  • Stratum Corneum: Keratins even after cell death
• Mutations in K5 or K14

  Can lead to blistering diseases such as Epidermolysis Bullosa Simplex, disrupting the structural integrity of the skin
• Desmosomes

  Facilitate strong cell-cell adhesion, critical in tissues experiencing mechanical stress like skin, heart, and epithelial layers of various organs. They link keratin filaments across adjacent cells, distributing force and preventing cell separation
• Hemidesmosomes


  Connect intermediate filaments to the extracellular matrix, anchoring cells to their substrate. This connection is vital for tissue stability, particularly in the skin and epithelial linings
• Role of desmin in smooth muscle

  Desmin links dense bodies within smooth muscle cells, providing structural integrity and resistance to mechanical forces during muscle contraction
• Role of desmin in skeletal muscle

  Desmin surrounds Z-lines and M-lines, contributing to the alignment and stabilization of sarcomeres, the contractile units of muscle fibers. This organization is critical for efficient muscle contraction and resilience to stress
• Neurofilaments

  Critical for the structural integrity and function of nerve cells, particularly in axons and glial cells
• Composition of Neurofilaments

  Consist of three primary subunits — NF-L (light), NF-M (medium), and NF-H (heavy). These subunits can form various heterodimers which assemble into the intermediate filaments of neurons
• Role of Neurofilaments in Neurons

  Essential for maintaining the correct diameter of axons, which is directly related to the rate at which nerve impulses (action potentials) are propagated. They provide mechanical strength to axons, resisting tensile forces that occur during nerve bending and stretching
• Nuclear Lamins

  Form a type of intermediate filament that provides structural support to the nuclear envelope and plays a role in organizing nuclear processes such as DNA replication and cell division
• Lamin Composition

  Include Lamin A, C (splice variants of the same gene differing at the C-terminus), and Lamin B. Lamin B is distinguished by a C-terminus that is covalently attached to the nuclear membrane via polyisoprenyloid lipids
• Nuclear Lamina Assembly

  Lamin dimers form higher-order structures that create a meshwork on the inner surface of the nuclear envelope. This meshwork is crucial for maintaining nuclear shape and rigidity
• Function of Nuclear Lamins

  Help tether heterochromatin (the transcriptionally silent regions of DNA) to the nuclear periphery, influencing gene expression patterns and stabilizing the genome
• Laminopathies

  • Mutations in lamin A are associated with a variety of genetic disorders, including Hutchinson-Gilford Progeria Syndrome, a premature aging condition resulting from defective lamin A
• Techniques such as electron microscopy and specific labeling (e.g., fluorescent tagging of DNA and lamins) provide insights into the organization of intermediate filaments within cells, illustrating their proximity to other cellular structures and their impact on cell function
• Ongoing research into intermediate filaments is vital for understanding their roles in health and disease, potentially leading to new therapeutic strategies for conditions linked to their dysfunction