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Molecular Cell Biology

Molecular Cell Biology. Intermediate Filaments Cooper. Introduction. Filaments 10 nm wide => “intermediate” Present in Metazoa / Animals i.e. not Plants or Unicellular Organisms Complex Gene Superfamily 70 in Human Genome Specific Expression at Different Times and Places.

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Molecular Cell Biology

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  1. Molecular Cell Biology Intermediate Filaments Cooper

  2. Introduction • Filaments 10 nm wide => “intermediate” • Present in Metazoa / Animals • i.e. not Plants or Unicellular Organisms • Complex Gene Superfamily • 70 in Human Genome • Specific Expression at Different Times and Places

  3. Intermediate Filament Biochemical Properties In Vitro • Very stable. Little subunit exchange. • Very strong. Filaments do not break. • MT’s strong but brittle • Actin weak

  4. Intermediate FilamentPotential Functions In Vivo • Mechanical Strength of Cytoplasm • Help a Layer of Epithelial Cells Resist Shear Stress - Filaments Connect to Cell-cell Junctions • Hold Nucleus in Center of Cell

  5. IntermediateFilamentStructure &Assembly

  6. Intermediate Filaments by EM:Filament Unraveling

  7. Classes of Intermediate Filaments

  8. Regulation of IF Assembly • Notoriously Stable • No Nucleotide • Filaments Move Little • Precursors Move More • Disassemble Somewhat during Mitosis • Phosphorylation by Cyclin-depen Kinase

  9. Vimentin Filaments in a Cultured Cell

  10. Vimentin • All Cells in Early Development • Cage Around Nucleus • Interacts with Mt’s • Vimentin Knockout Mouse • Initially normal at gross inspection • Cultured cells have altered properties of uncertain significance

  11. FRAP of Vimentin vs. Keratin in One Cell Left: Vimentin (Green) Right: Keratin (Red) 10 min time intervals

  12. Dynamics of Keratin Particles in Periphery 11 micrometers over 10 minutes 18 micrometers over 10 minutes

  13. Desmin • Expressed in Muscle • Elastic Elements to Prevent Over-stretching • Connects / Aligns Z lines • Knockout Mouse - Deranged Myofibril Architecture

  14. Keratins • Expressed in Epithelia • Keratin Filaments Connect to Desmosome and Hemidesmosomes • Differentiation of Epidermis includes Production of Massive Amounts of Keratin • Provides Outer Protection of Skin • Composes Hair, Nails, Feathers, etc.

  15. Density of Keratin Filaments in Outer Epidermis Layers

  16. Keratin Mutations are Basis forHuman Epidermal Diseases • Structure/Function Analysis of Keratin Assembly • Point Mutation in Terminal Domain Fails to Assemble • Mutant is Dominant, even in Low Amounts, in Cultured Cells and Mice

  17. Epidermolysis Bullosa Simplex Wild-type Mutant

  18. Keratins and EBS

  19. Neurons • Neurofilament H, M, L Copolymer • Prevent Axon Breakage • Diseases with Clumps of Neurofilaments • Superoxide dismutase model for ALS • Clumps are secondary, not causative

  20. Neurofilament Transport in Axons Photobleached Zone in the Middle

  21. Neurofilament Transport in Axons Photobleached Zone in the Middle

  22. Lamins • Square Lattice on Inner Surface of Nuclear Membrane • Present in Metazoans (Animals, not Plants or unicellular organisms) • Mitosis Breakdown • Phosphorylation of A & C by Cyclin-depen Kinase • B remains with Membrane • Mutations Cause Accelerated Aging Diseases • Progerias - Dominant Mutations

  23. EM of Nuclear Lamina Nuclear Pores

  24. End

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