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Transcript
BIOS 341 Lecture 22 Cell Junctions and cell adhesions, page 1 Cells in their social context Cell Junctions Historically studied morphologically Model of an intestinal wall Occluding junctions form a selective permeability barrier across epithelial sheets Tight junctions, also known as Zonula occludens (ZO) Occluding junctions in vertebrates provide a barrier role in most epithelia. They prevent protein and lipid diffusion in the plasma membrane allowing for polarization i.e. Apical vs. basolateral membrane. Tight junctions also provide a variable permeability barrier between cells. The strength of this permeability barrier is cell type dependent. For example, bladder epithelial tight junctions are 104 X less permeable to inorganic ions like Na+ than intestinal epithelia. BIOS 341 Lecture 22 Cell Junctions and cell adhesions, page 2 The role of tight junctions in transcellular transport Barrier function of tight junctions Tight junction structure and function Sealing strands completely encircle each cell in the epithelial sheet. Permeability decreases with an increase in the number of sealing strands BIOS 341 Lecture 22 Cell Junctions and cell adhesions, page 3 Higher resolution model of tight junctions Claudin and occludin also bind to peripheral membrane proteins called ZO proteins that anchor the sealing strands to the actin cytoskeleton BIOS 341 Lecture 22 Cell Junctions and cell adhesions, page 4 Septate junctions Occur in invertebrates like Drosophila. They are functionally similar to tight junctions, but differ in structure and appearance. Anchoring Junctions connect the cytoskeleton of a cell to the cytoskeleton of its neighbors or to the extracellular matrix Anchoring junctions provide mechanical strength. This is especially important to tissues encountering severe mechanical stress like heart, muscle, and skin. They connect the cytoskeleton to neighboring cells or the extracellular matrix. Anchoring Junctions are composed primary of two main classes of proteins: Intercellular anchor proteins and transmembrane adhesion proteins. Types of anchoring junctions Adherens junctions Desmosomes Hemidesmosomes Focal Adhesions Anchoring junctions in epithelia BIOS 341 Lecture 22 Cell Junctions and cell adhesions, page 5 Main classes of anchoring junction protein components Adherens junctions connect actin filaments from cell to cell They can also form adhesion belts (zonula adherens) in epithelial layers. The transmembrane adhesion proteins belong to the cadherin family. The intracellular anchoring proteins include: Catenins, Vinculin and α-actinin. Cells must be attached by adherens junctions for tight junctions to form. Adherens junctions BIOS 341 Lecture 22 Cell Junctions and cell adhesions, page 6 Uses of adherens junctions in development Contraction of adherens junctions is mediated by myosin motor proteins with shortening of the intervening actin filaments Desmosomes connect intermediate filaments from cell to cell The type of intermediate filament attached is cell type specific, but they are keratin filaments in most epithelial cells. The transmembrane adhesion proteins belong to the cadherin family and are called desmoglein and desmocollin. The intracellular anchoring proteins are usually plakoglobin and desmoplakin. Desmosome BIOS 341 Lecture 22 Cell Junctions and cell adhesions, page 7 Anchoring junctions formed by integrins bind cells to the extracellular matrix: Focal adhesions and hemidesmosomes Hemidesmosomes “Half desmosomes” that connect intermediate filaments to the basal lamina. These structures are morphologically similar to desmosomes but use transmembrane adhesion proteins belong to the integrin family. In this case, the extracellular domain of the integrin binds to substrate on which the cell is growing through laminin (more later). The primary intracellular anchor protein is called Plectin. Desmosomes and hemidesmosomes Focal Adhesions connect actin filaments to the basal lamina The transmembrane adhesion proteins belong to the integrin family. The uniques aspect of this junction is that focal adhesions are regulated assemblies that are altered during cellular movement. actin=green vinculin=red Summary of anchoring junctions BIOS 341 Lecture 22 Cell Junctions and cell adhesions, page 8 Gap junctions allow small molecules to pass directly from cell to cell Gap Junctions Most cells in most tissues are in communication with neighboring cells by gap junctions They are made up of membrane-spanning channel-forming proteins called connexins. The channels or connexons have a maximal pore size or ~ 1.5nm that allow the passage of small molecules such as inorganic ions, sugars, amino acids, nucleotides, etc., but not proteins. Gap junction permeability A gap junction connexon is made up of six transmembrane connexin subunits Anatomy of a Gap Junction Each connexin monomer has four membrane-spanning segments. Humans have 14 different connexin genes. Six monomers assemble into a connexon and different connexin subunit assemblies can produce different connexons. The connexons from adjacent cells interact to form an intercellular channel BIOS 341 Lecture 22 Cell Junctions and cell adhesions, page 9 Gap junctions have diverse functions Electrical synapse Direct coupling allows the propagation of an action potential from one cell to another without the need for a chemical intermediate (much faster) Sharing of metabolites helps coordinate activities Glycogen breakdown in response to hormonal stimulation in the liver Hepatocytes not directly stimulated by hormone (potentially several cell layers away from a capillary and the source of the hormone) detect a signal by sharing a second messenger through gap junctions Communication during development Communication between granulosa cells and the oocyte through gap junctions is apparently important for oocyte maturation. Mutations in connexin37 cause infertility and disruption in the development of both the oocyte and granulosa cells. BIOS 341 Lecture 22 Cell Junctions and cell adhesions, page 10 The permeability of gap junctions can be regulated The primary regulators of gap junction permeability are pH and cytosolic Ca2+ concentration as well as extracellular signals including neurotransmitters like dopamine. Why is it necessary to regulate permeability? Cells need a way to close down these connections to prevent widespread damage when one participant is damaged. Summary of vertebrate epithelia junctions In plants, plasmodesmata perform many of the same functions as gap junctions Plasmodesmata Since plants have a rigid cell wall, a specialized structure is required to bridge it. BIOS 341 Lecture 22 Cell Junctions and cell adhesions, page 11 Cell Adhesions Historically studied biochemically Cell Adhesion Molecules (CAMs) Cell surface transmembrane proteins that are responsible for cell-cell adhesion and cell-matrix adhesion. Some are Ca2+-dependent, while others are Ca2+-independent. CAMs were initially identified using antibodies to cell surface molecules that were capable of inhibiting cell-cell adhesion in the test tube. Cadherins mediate Ca2+ dependent cell-cell adhesion Present in adherens junctions and desmosomes and found in virtually all cells and tissues BIOS 341 Lecture 22 Cell Junctions and cell adhesions, page 12 Structure and function of cadherins Types of cell-cell adhesion Cadherins mediate cell-cell adhesion by a homophilic mechanism Tissue culture cells (that normally do not express N or E-cadherins) can be made to express either N- or E-cadherin. The resulting population self selects based on homophilic interaction of the individual cadherins. BIOS 341 Lecture 22 Cell Junctions and cell adhesions, page 13 Classical cadherins are linked to the actin cytoskeleton by catenins Selectins mediate transient cell-cell adhesions in the bloodstream Selectins are cell surface, carbohydrate binding proteins (lectins) that function in Ca2+-dependent cellcell adhesion in the bloodstream. They are named according to the cell type in which they are expressed. While blood cells express L-selectins, platelets express P-selectins and activated endothelial cells express E-selectins The structure and function of selectins Selectins are responsible for white blood cell adherence to endothelial cells necessary for tissue migration. The lectin-binding domain is specific for each class of selectin. BIOS 341 Lecture 22 Cell Junctions and cell adhesions, page 14 Members of the immunoglobulin superfamily of proteins mediate Ca2+ independent cell-cell adhesion Neural cell adhesion molecules (N-CAMs) Intercellular cell adhesion molecules (I-CAMs) Structure and function of N-CAMs Multiple types of cell-surface molecules act in parallel to mediate selective cell-cell adhesion Summary of junctional and nonjunctional adhesive mechanism Nonjunctional contacts may initiate cell-cell adhesions that junctional contacts then orient and stabilize