Cell-Cell Interactions PP notes

Types of tissues in animals

  • Epithelium: sheets/layers of cells with polarized functional domains, apical and basal

    • lines organs

    • outer layer of skin

  • Connective tissue: loosely organized fiber/gel in which cells are attached to each other

    • cartilage, bone, blood

Adhesive Junctions

Adhesive junctions anchor the cytoskeleton to the cell surface, relying on specialized adhesion proteins which can interact with the other extracellular proteins on neighboring cells

Homophillic interactions involve cells with identical receptors interacting with each other, while heterophilic interactions have cells with different receptors. Many receptors also interact with the cytoskeleton via linker proteins.

  • Cells assemble/disassemble in response to cellular events

  • Adhesion proteins are recycled through endocytic and exocytic pathways

  • Adhesion proteins are sites of assembling signaling complexes and cytoskeletal structures

  • Cell adhesion is coordinated with cell signaling, movement, proliferation, and survival

Adherens Junctions

  • Cadherin-mediated junctions that interact with actin

  • Prominent in epithelial cells

  • Cadherins

    • repeats in extracellular domain

    • transmembrane domain

    • varying cytosolic ends

    • Structure diagram

  • E-Cadherin

    • 5 repeats on extracellular domain, two E-cadherin molecules can interact

    • associate in pairs in a calcium dependent manner

    • cytosolic portions interact with cytoskeleton

  • Beta-Catenin and Alpha-catenin

    • B-catenin binds to cytosolic tail of cadherin

    • bound by a-catenin, which recruits actin to the junction

    • a-catenin stretches and binding sites become available

    • vinculin can bind to sites and strengthen connection to F-actin

  • p120 Catenin

    • binds to cytoplasmic tail of cadherins near the plasma membrane

    • regulates stability of cadherins and how quickly they are endocytosed

  • Epithelial-mesenchymal transition (EMT)

    • breakdown of epihelium into loosely organized mesenchyme cells

    • accompanied by changes in cadhein expression

    • occurs in cancer cells which metastasize

Desmosomes

  • button-like points of strong adhesion between adjacent cells in tissue

    • structure diagram

  • provide structural integrity

  • abundant in cells under mechanical stress

  • Desmosome core: extracellular space between two connected cells

  • desmosomal cadherins are desmocollins and desmogleins

  • linker proteins bind to domains and link to cytoskeleton

  • Plakoglbin binds desmocolin and desmoplakin

    • desmoplakin attaches intermediate filaments

  • p120ctn family is plakophilin can bind to cadherins and desmoplankin

  • thick plaque with linker proteins and intermediate filaments located between the membrane of adjoined cells

Lectins

  • carbohydrate-binding proteins

  • promote cell-cell adhesion by binding to sugars at outer cell surface

  • cand bind to carbs on two different cells, linking them together

Cell Adhesion Molecules (CAMs)

  • CAMs are members of the immunoglobulin super family (IgSF)

  • well-organized loops like immunoglobulins in their extacellular domains

  • homophilic interactions occur via domains

  • ex. Neural cell adhesion molecule, N-CAM

Leukocyte Adhesion

  • Leukocytes interact with platelets or blood vessels during inflammation

  • reactions are mediated by selectins

    • L-selectin - leukocytes

    • P-selectin - platelets

    • E-selectin - endothelial cells of blood vessels

  • stable adhesions at site of inflammation are mediated by integrin and ICAM

Tight Junctions

Tight junctions form a seal between two cells, leaving no space between their plasma membranes. They form a continuous belt around the apical (top) ends of lateral surfaces on each cell, and molecules cross the cell layer by passing through the cells

Tight junctions have several transmembrane proteins such as occludin and junctional adhesion molecules (JAMs), as well a claudins.

Function of Claudins

  • proteins with 4-membrane spanning domains

  • interlock in adjacent cells to form tight seal

  • large extracellular loop forms ion-selective pores to allow passage of specific ions

    • called paracellular transport

Tight junctions block lateral movement of lipids and proteins in the plasma membrane

  • lipids blocked only in outer monolayer

  • integral membrane proteins completely blocked

Gap Junctions

A gap junction is a region where the plasma membranes of cells are in contact, with a very small gap in between. The gap includes small passages between the cells, allowing small molecules and ions to pass directly from one cell to another

In a gap junction, the plasma membranes of adjacent cells are connected by hollow cylinders called connexons. Each connexon has 6 subunits of connexin proteins, forming a circle. (innexin and invertebrates). Every connexon has a channel about 3nm wide, only allowing small molecules to pass through.

Extracellular Matrix (ECM)

The extracellular matrix in animal cells is crucial for tissue structure and function, as it takes on several different roles:

  • Bone consists of a rigid ECM containing a small number of interspersed cells

  • Cartilage is tissue mostly made of matrix materials more flexible than bones

  • Connective tissue which surrounds glands/blood vessels is gelatinous, containing interspersed fibroblast cells

ECM consists 3 classes of molecules:

  • Structural proteins

    • collagens, elastins

    • strength & flexibility

  • Protein-polysaccharide complexes

    • proteoglycans

    • provide matrix

  • Adhesive glycoproteins

    • fibronectins, lamins

    • allow cells to attach to matrix

Collagens

  • most abundant in ECM in animals

  • secreted by cells in connective tissues, such as fibroblasts

  • rigid triple helix of intertwined polypeptides

    • high glycine and rare amino acids

    • glycine spacing important for helix

  • Collagen fibers are composed of fibrils

    • fibrils made of many collagen molecules, twisted into chains of three

  • In ER lumen, 3 chains form triple helix procollagen

    • short, nonhelical sequences at ends

    • nonhelical ends cleaved by procollagen peptidase outside the cell

    • spontaneously associate into fibrils, fibers

  • stability of fibrils reinforced by hydrogen bonds between amino acids (hydroxylysine and hydroxyproline)

    • form crosslinks between/within collagen molecules

Elastins

  • provide elasticity to ECM by fibers composed of elastins

  • rich in glycine and proline, crosslinked by bonds between lysine residues

  • tension causes network to stretch

  • release of tension causes molecules to relax

Collagen and elastin fibers are combined in a gel-like network of proteoglycans, glucoproteins, and glycosamionglycans attached to a protein

Glycosaminoglycans (GAGs) are large carbohydrates with repeating disaccharide units

  • most common types are chondroitin sulfate, keratan sulfate, and hyaluronate

  • repeating unit has one amino sugar

    • N-acetylglucosamine (GlcNAc)

    • N-acetylgalactosamine (GalNAc)

  • other sugar is sugar or sugar acid

    • galactose (Gal)

    • glucuronate (GlcUA)

  • amino sugar has 1+ sulfate attached

  • hydrophillic, attract water and cations

  • forms gelatinous matrix where collagen and elastin are embedded

Proteoglycans

  • GAGs in ECM covalently bound to proteins form proteoglycans

  • each has number of GAG chains attached along length of a core protein

  • vary in size depending on core protein and length of GAG chains

  • integral components of plasma membrane    

    • core polypeptides embedded in membrane

    • covalently linked to membrane phospholipids

Hyaluronate

  • occurs both as backbone of cartilage proteoglycans and a free molecule

  • lubricating properties

  • most abundant where friction needs to be reduces, ex. joints

Fibronectins

  • family closely related glycoproteins in ECM

  • RNA transcribed from fibronectin gene processed to produce many varients

  • can be soluble in blood/body fluids, insoluble fibrils in ECM, and intermediate associated with cell surfaces

  • two large suvunits linked by C-terminal, 2 disulfide bonds

    • folded into rodlike domains

    • several domains bind 1+ ECM macromolecules (collagen, heparin, fibrin)

    • other domains recognize & bind cell surface receptors via RGD (arg-gly-asp) sequence

  • acts as bridging molecule between cells and ECM

  • cell migration

  • soluble form is plasma fibronectin

    • promotes blood clotting

Basal Lamina

  • thin sheet of specialized extracellular material

  • underlines epthelial cells

  • surround muscle cells, fat cells, and schwann cells

  • major adhesive glycoprotein is laminins

  • structural support and permeability barrier

  • contain type IV collagen, proteogluycans, laminins, and nidogen

  • can alter properties of basal lamina by secreting enzymes in it

    • metalloproteinases (MMPs) degrade ECM locally, allowing cells to pass through (require metal cofactors)

Laminin

  • 3 long polypeptides, α, β, and γ

  • disulfide bonds hold PP together in shape of cross

  • several domains, such as binding sites for type IV collagen, heparin, heparin sulfate and entactin

    • receptors on cell surfaces

Integrins

  • large family of cell surface receptors

  • bind to fibronectins or laminins

  • integrate the cytoskeleton with ECM

  • consist of 2 large transmembrane polypeptides, α & β

  • differ in binding specificity and subunit size

  • extracellular parts of subunits form binding sites

    • specificity depends on alpha unit

  • many types of subunits, resulting in many types of integrin heterodimers

  • recognize RGD sequences in ECM glycoproteins

  • tails interact with cytosolic proteins that link integrins to cytoskeleton

  • focal adhesions attach migraotory and non-epithelial cells (fibroblasts) to ECM

    • contain clustered integrins

    • interact with bundles of actin filaments

  • interact with signaling pathways

    • MAP kinase activation induces integrin clustering

    • act as receptors for intracellular signaling

Hemidesmosomes

  • found in epithelial cells

  • contain alpha-6-beta-4 integrin

    • attached to keratin, an intermediate filament

  • linker proteins form a dense plaque to connect integrins to cytoskeleton

  • plankin family are linker proteins

    • pectin attaches keratin to integrins

    • BPAG2 and its plakin, BPAG1, bridge keratin and laminin

Anochorage-dependent growth requires cells to be attached to a substratum, which involves the activation of intracellular pathways following integrin clustering.

A costamere is an attachment structure at the surface of striated muscle which align with the Z discs, containing the protein dystrophin.

  • Dyrstrophin mutation causes muscle disease

  • acts as a spring

  • links to laminin, connecting costaneres to ECN

  • interacts with a complex including integral membrane proteins