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Lecture 16

Lecture 16 & 17: "Intermediate Filaments II"

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Biology 2382B
Robert Cumming

Cell Biology Lectures No. 16 & 17: Intermediate Filaments II th Monday March 11 , 2013 The Structure Of Intermediate Filaments: -The simplest unit of intermediate filaments are relatively large proteins with polarity (one C-terminus end and one N-terminus end) and head, rod and tail domains. Two of these proteins form a dimer, which has polarity, is not the building block of intermediate filaments. The building block is a tetramer (two dimers), which doesn’t have any polarity (ends are the same). Tetramers then come together (polymerize without requiring energy sources like ATP and GTP) to form a protofilament. Note that for this course, the distinction between protofilaments and protofibrils isn’t testable. For your amusement, tetramers aggregate end to end and laterally into a protofibril and in mature intermediate filaments, four protofibrils form a protofilament. The Dynamic State Of Intermediate Filaments: -Intermediate filaments, though not as dynamically unstable as actin and tubulin, does polymerize and depolymerize. This fact of exchanging (adding or removing) IF tetramers was determined through experiments where biotin-labelled Type I keratin was injected into epithelial cells, resulting in these labeled proteins being incorporated into the already existing keratin cytoskeleton. This also shows that the IF network is dynamic and does not use energy. The intermediate filament cytoskeleton (like actin and tubulin, just not as quickly) has to be able to change because the cell will change its functions and shape over time. During mitosis, the breakdown of the nuclear membrane in prophase is critical. This state can be achieved through the disassembly of lamin filaments that form a meshwork supporting the nuclear membrane. The phosphorylation of (a serine residue on the N-terminal domain of) nuclear lamins by a mitotic cyclin-dependent kinase (that becomes active early in prophase of mitosis) induces the disassembly of intact intermediate filaments and prevents their reassembly. Mutated or absent serine residues on lamin (in this case lamin A) would discourage this crucial disassembly. Later in telophase mitosis, the removal of these phosphates by specific phosphatases promotes lamin reassembly, which is critical to the re-formation of a nuclear envelope around the daughter chromosomes. Thus, the balance between the opposing actions of kinases and phosphatases in the depolymerization and polymerization of lamins (and other IF proteins) is critical to the cell cycle. Intermediate Filament-Associated Proteins (IFAPs): -Intermediate Filament-Associated Proteins (IFAPs) are a group of proteins that co-purify with intermediate filaments. One particular family of IFAPs include plakins, which are involved in attaching intermediate filaments to other structures. Such notable examples of plakins are plectins that work to cross-link IF proteins like vimentin with microtubules to achieve optimal tensile strength. Functions Of Intermediate Filaments (Membrane): -As mentioned previously, lamins support the nuclear membrane as a meshwork of intermediate filaments. This network is formed by A lamins and B lamins linked to the nuclear lamina (a fibrillar network inside the nucleus of a eukaryotic cell composed of intermediate filaments and membrane- associated proteins) through a type of IFAP known as lamin-associated polypeptides (LAP2). This demonstrates how intermediate filaments are important in their function of providing structural support necessary for cell shape (e.g. vimentin links to ankyrin that mediates the attachment of integral membrane proteins to the spectrin-actin based membrane skeleton). In transgenic mice carrying a mutant keratin gene, individuals exhibit skin blistering (ripping of the epidermis) due to their weak skin integrity. This is because IF proteins are critical in their function of promoting tissue integrity through linkage, especially in the skin. Functions Of Intermediate Filaments (Junctions): -A sheet of epithelial cells comprising the epidermis must stick to each other and to the extracellular matrix (ECM). Patches in between cells and in between cells and the ECM (known as junctions) are linked to the cytoskeleton, and to intermediate filaments in particular. Some intermediate filaments (such as plakins) associate with keratin filaments to link them to desmosomes (junctions between epithelial cells that provide stability to a tissue) and hemidesmosomes (located at regions of the plasma membrane where intermediate filaments are linked to the extracellular matrix). Cell Junctions & Cell Adhesions: -Intermediate filaments and actin play a critical role in cell adhesion because they are cortical and are found mostly at the plasma membrane (where all the adhesions are occurring). Microtubules are excepted from this as they are located deep in the cell (near the nucleus) and almost never come near the plasma membrane. Cell adhesions are important for allowing cells to not only stick together, but also to communicate and engage in special functions. Cell junctions have specific roles in cell-cell function and do “glue” cells together, but don’t provide strength (not too many cytoskeletal components binding to junctions), which is provided by proper cell adhesion molecules (CAMs). The epithelial cell has an apical surface (that is exposed to the outside environment) like microvilli and cilia and a basal surface (where they are attached to tissues). Gap Junctions & Tight Junctions: -Cells have gap junctions (gap or pores) so they allow things to move from one cell to another cell, providing a channel that allows cells to communicate with each other. These gap junctions consist of connexin proteins, where each interacting cell takes up 6 connexins (collectively a connexon) to form a gap junction. Many types of gap junctions can be created to allow molecules of different sizes through the use of different types of connexons (usually only small molecules pas through gap junctions). Gap junctions are regulated by Ca because as epithelial cells (which are all linked by gap junctions) form a barrier, damaged (leaky) gap junctions could potentially drain the important contents and fluids of the entire epithelial sheet. Calcium ions are used as a mechanism for shutting down gap junctions if they are damaged to pre2+nt exposing the whole network of cells to intrusion by nefarious biological agents. Since free Ca is in very short supply inside the cell, high levels of extracellular calcium ions come in to close up the gap junction. -Tight junctions glue plasma membranes of neighbouring cells together and allow the formation of a barrier. This is seen in epithelial cells have to form a barrier to prevent things from getting past them (you want the intestine to absorb nutrients and you don’t want anything sneaking past the cells). Thus, tight junctions force everything to go through the epithelial cells and also divide the individual cell up into an apical membrane (above the tight junction) and basa
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