extracellular matrix (edited)

7/31/2019 Extracellular Matrix (Edited)

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Extracellular Matrix- an organized network of extracellular materials thatis present beyond the immediate vicinity of theplasma membrane-in animal cells, it takes on a remarkable variety of forms in different tissues

-has different roles:1. provide structural support2. it also influences properties such as tissue

excitability, cell shape and movement and

development of specialized cellularcharacteristics


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Functions of ECM Scaffold to

stabilize thephysicalstructures of tissues

Regulate cellbehavior Influence cells

survival,development,migration,proliferation,shape andfunction

Connective tissue underlying anepithelial cell sheet. It consistlargely of ECM that is secreted by

the fibroblasts.


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ECM is always consists of the same three classes of molecules:1. collagens and elastins- structural proteins which give the

ECM its strength and flexibility

2. proteoglycans (protein-polysaccharide complex)-providethe matrix in which the structural molecules areembedded

3. fibronectins and laminins- adhesive glycoproteins

- attaches cells to the matrix

Kind of Organism

ExtracellularStructure

Structural Fiber Components of hydrated matrix

Adhesivemolecules

Animals ExtracellularMatrix(ECM)

Collagens andelastins

proteoglycans Fibronectins andlaminins

Plants Cell wall cellulose Hemicellulosesand extensins

pectins

Table 11. Extracellular Structures of Eukaryotic Cells


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Collagens are responsible for the strength of the extracellular complex


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Collagens are:

insoluble, extracellular glycoproteins

found in all animals the most abundant proteins in the human body

They are essential structural components of all connective tissues , such as cartilage bone tendons ligaments fascia skin

19 types of collagens have been found (so far) in humans. The major ones are:

Type I . The chief component of tendons, ligaments, and bones.

Type II . Represents more than 50% of the protein in cartilage . It is also used

to build the notochord of vertebrate embryos.
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Type III . Strengthens the walls of hollow structures like arteries,the intestine, and the uterus.

Type IV . Forms the basal lamina of epithelia. (The basal lamina

is often called the basement membrane, but is not related to lipidbilayer membranes.) A meshwork of Type IV collagens providesthe filter for the blood capillaries and the glomeruli of the kidneys.

The other 15 types are probably equally important but they aremuch less abundant
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Primary Structure of Collagens The basic unit of collagens is a polypeptide consisting of therepeating sequence(glycine (Gly) - X - Y)n

where X is often proline (Pro) and Y is often hydroxyproline (proline to which an -OH group is added after synthesis of the

polypeptide).

Secondary and Tertiary Structure The resulting molecule twists into an elongated, left-handed helix(NOT an alpha helix ). When synthesized, the N- terminal and C-terminal of the polypeptide have globular domains, which keepthe molecule soluble.As they pass through the endoplasmic reticulum (ER) and Golgiapparatus ,
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The molecules are glycosylated. Hydroxyl (-OH) groups are added to the "Y" amino acid. S-S bonds link three chains covalently. The three molecules twist together to form a triple helix .

In some collagens (e.g., Type II), the three molecules are identical (the productof a single gene). In other collagens (e.g., Type I), two polypeptides of one kind(gene product) assemble with a second, quite similar, polypeptide, that is theproduct of a second gene.

When the triple helix is secreted from the cell (usually by a fibroblast), theglobular ends are cleaved off. The resulting linear, insoluble moleculesassemble into collagen fibers . They assemble in a staggered pattern that givesrise to the striations seen in this electron micrograph. (Type IV collagens are anexception; they form a meshwork rather than striated fibers.)


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Inherited Diseases Caused by Mutant Collagen Genes

1. Brittle-bone disease ("osteogenesis imperfecta") Caused by a mutation in one or the other of the two genes whoseproducts are used to make Type I collagen. Like all the inheritedcollagen diseases, this one is inherited as a dominant trait . Thereason: even though one collagen allele is normal, the assemblyof the normal gene product with the mutant product produces

defective collagen fibers.2. Some forms of dwarfism Caused by mutations in a Type II collagen gene.3. Rubber-man syndrome

Caused by a mutations in a Type I collagen gene. The subject hashyperextensible joints, tendons, and skin. (This inherited disorder represents one type of Ehlers-Danlos syndrome.)4. Another type of Ehlers-Danlos syndrome Is caused by mutations in the gene for Type III collagen. Patientsare at risk of rupture of major arteries or the intestine. 2.
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Ehlers-Danlos syndrome

Defect in synthesis or structure of fibrillar collagen(mutations have been found in collagen types I, III,IV)

Skin hyperextensibility, joint laxity, fragile skin and vessels,poor wound healing


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Elastins .- is a protein in connective tissue that is elastic and

allows many tissues in the body to resume their shape after

stretching or contracting. Elastin helps skin to return to itsoriginal position when it is poked or pinched.

- provide flexibility to skin, arteries, and lungs. (Theseare not glycosylated.)

*Collagen and Elastin Fibers are embedded in a matrix of proteoglycans

Stretching a networkof

elastin molecules
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Proteoglycans- glycoproteins in which a large number of glycosamino-

glycans(GAGs) are attached to a single protein molecule.

-also called mucoproteins-GAGs (the main carbohydrate components of proteoglycans)

*also called mucopolysaccharides*form hydrated gels* have four types:

Hyaluronan Chondroitin sulfate and

dermatan sulfate Heparan sulfate Keratan sulfate


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slowing their flow. Because of their high water content, proteoglycannetworks are quite resistant to compression and regain their shapequickly

-contributes to the resilience and pliability of cartilage-important role of proteoglycans is to trap water molecules, thus


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Hyaluronan is a major polysaccharidecomponent of the ECM

Present in all tissues and bodyfluids

Simplest GAG Regular repeating sequence of up

to 25,000 disaccharide units No sulfated sugars Not linked to a protein

Abundant in early embryos Resist compressive forces in

tissues and joints (lubricating

properties) Space filler for embryo

development Provide space for cell migration

(formation of organs) Wound healing


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Functions of Hyaluronan Resists compressive forces in joints and tissues In osteoarthritis, decreased concentration and

decreased molecular weight of intra-articularHA.

FDA d HA f


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FDA approved HA forcosmetic use in humans- 2003


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Proteoglycans and Adhesive Glycoproteins Anchor Cells to theExtracellular Matrix

1. Cells are anchored to the ECM by proteoglycan linkages2. Direct links between the ECM and the plasma membrane are reinforced by

a family of ADHESIVE GLYCOPROTEIN-bind proteoglycans and collagen molecules to each other and toreceptors on the membrane surface

-the two most common kinds:a. Fibronectinsb. Laminins

*many of the membrane receptors to which glycoproteins bind belong to atransmembrane proteins called integrins.


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Fibronectins Bind cells to the Matrix and Guide Cellular Movement

Fibronectins-most common adhesive glycoprotein in the ECM-widely distributed throughout the aimal kingdom-occur in a) soluble form in blood and other body fluids

b) as insoluble fibrils in the extracellular matrixc) intermediate form loosely associated with cell surfaces

* Though they differ in solubility and location they are encoded by the same gene

-Dimer with disulfide bonds at one end*Similar but not identical

*Made from the same gene but differently splicedmRNAs


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Structure of a fibronectin dimer


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Isoforms of Fibronectin


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A. Effects of Fibronectin on Cell Shape

Because the orientation and organization of the cytoskeletal networkare important in determining the shape of the cell, fibronectin is thoughtto be significant in the maintenance of cell shape.(* a possible involvement of fibronectin in cancer is suggested by theobservation that many kinds of cancer cells are unable to synthesizefibronectins, with an accompanying loss of normal cell shape anddetachment of the cell from the ECM. If such cells are supplied withfibronectin, they often return to their normal shape, recover their ability

to bind to the ECM and are no longer malignant).

Fibronectin Actin


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B. Effects of Fibronectin on Cell Movement-involved in cellular movement such as cell migrations thatoccur during early embryonic development.-pathways followed by migrating cells are rich in fibronectin (itsuggests that such cells are guided by binding to fibronectin moleculealong the way).

C. Effects of Fibronectin on Blood Clotting andWound Healing-plasma fibronectin

*soluble form of fibronectin

*involved in blood clotting and perhaps in wound healingHow?: Fibronectin promotes blood clotting because it has several

binding domains that recognize fibrin(the blood-clottingprotein) and can attach blood platelets to fibrin as theblood clot forms.-also thought to guide cells of the immune system as they


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migrate into the wounded areas thus promoting wound healing.

Laminins Bind Cells to the Basal Lamina

Laminins- another major adhesive glycoprotein present in the ECM- found mainly in the basal laminae-consist of three different polypeptide chains linked bydisulfide bonds and organized into a molecule resemblinga cross with three short arms and one long arm- like fibronectin, extracellular laminins can greatly influence

a cells potential for migration, growth and differentiation


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Basal laminae


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Properties of Basal Lamina1. serves as structural support2. maintains tissue organization

3. permeability barrier that regulates the movement of moleculesas well as of cellseg.* In the kidney- basal lamina functions as filter that allows small

molecules but not blood proteins to move from the bloodinto the urine.

* the basal lamina beneath epithelial cells prevents passage of underlying connective tissue cells into the epithelium butpermits migration of WBCs needed to fight infections(the effect of basal lamina on cell migration is of special

interest because of the recent finding that the surfacesof some cancer cells are enriched in binding sites forlaminin- the resulting increase in the ability of CC to bindto BL may facilitate their movement thru the structure andallow them to migrate from one region of the body toanother).


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-Basal lamina also organizes proteins in the membranes of adjacentcells and is involved in the induction of cellular differentiation andthe regeneration of injured tissue

Regeneration experiments indicating the special character of the junctional basal lamina at a neuromuscular junction


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Integrins are Cell Surface Receptors that Bind ECM Constituents

Integrins - receptor glycoproteins which belong to the family of trans-membrane proteins- has a role in integrating the cytoskeleton with the intracellularmatrix-very important receptors bec they are the 1 o means by whichECM proteins such as collagen, fibronectin, and laminin bind

to cells and influence cellular functions as well as structure.


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Integrins

The subunit structure of an integrin cellsurface matrix receptor


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Integrins


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Cells regulate the activity of their integrins


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Cell Interactions, theExtracellular Matrix,

and Cell Wall


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Cell-Cell Recognition and Adhesion

-the integrity of multicellular organisms depends on theability of individual cells to associate in precise patterns to

form tissues, organs and organs systems. Such orderedinteractions require that individual cells be able torecognize, adhere to and communicate with each other.

Cell Cell Interactions


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Cell-Cell Interactions

Introduction Cell Adhesion Molecules (CAMs)

Cadherins Selectins N-CAMs

Cell-cell Interaction Types of Junctions

Tight (occluding) junctions Anchoring junctions

Adherens Desmosome Hemidesmosome Septate junctions (invertebrates only)

Communicating Junctions Gap Junctions Plasmodesmata (plants only)


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INTEGRATING CELLS INTO TISSUES Multicellular organisms organize their cells to

coordinate essential activities. Cells elaborate specialized connections between

themselves and with their environment, oftenclustering to form specialized junctions.

Integral membrane proteins, cell- adhesion molecules(CAMs), adhere cells tightly and specifically withcells of the same or similar type and allow for rapidcommunication.

Animal cells also elaborate a complex network of proteins and carbohydrates, the extracellular matrix(ECM), that creates a special environment betweenthe cells.


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Schematic overview of major adhesiveinteractions that bind cells to each other and tothe Extracellular Matrix (ECM)


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Cell Adhesion Molecules (CAMs)

Binds cells together Homophilic adhesion

between cells of a single type

Heterophilic bindingbetween cells of differenttypes

The cytosol-facing domain if the CAMs are usually connected to elements of thecytoskeleton

C ll C ll d C ll M t i Adh i M l l


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Cell-Cell and Cell-Matrix Adhesion Molecules(CAMs)

Five major classes: some homophilic; someheterophilic

T b dh i t i li k th


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Transmembrane adhesion proteins link theCytoskeleton to Extracellular Structures:

Cell-cell adhesions usually mediated by cadherins Cell-matrix adhesions usually mediated by

integrins Internal linkage to cytoskeleton is mediated by

intracellular anchor proteins


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Adhesive Proteins: Cadherins Calcium dependent cell-cell adhesion

glycoproteins Over 40 different forms expressed in

tissue specific fashion Antibody to cadherin or removal of

calcium leads to dissociation of

epithelial cells and failure to formdesmosomes and gap junctions

Prefers homophilic binding (can thereby mediate cell sortin


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The C-terminal cytoplasmic domain associates with the cytoskeleton

N-terminal extracellular domain forms dimers and,through homophilic, interactions forms tetramersEach cadherin has a characteristic tissue

distribution

The Cadherin superfamily includes


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The Cadherin superfamily includeshundreds of different proteins

Take their name fromtheir dependence oncalcium

Extracellular domaincontaining multiplecopies of the cadherinmotif

Intracellular portions varied

Adhesive and signalingfunctions

C dh i M di C 2+ d d


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Cadherins Mediate Ca 2+ - dependentcell-cell adhesion in all animals:

Main adhesion molecules holding cellstogether in early embryonic tissues


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Cadherins

Ca2+

dependent cell-cell adhesion E-cadherin: epithelial cells N-cadherin: nerve, muscle, fibroblast, &

lens cells P- cadherin: placenta, epidermis, breast

epithelium

VE-cadherin: endothelial cells Co-receptor for vascular endothelial growth

factor (VEGF) which binds to a receptor fortyrosine kinase (signal transduction)

Cadherins mediate homophilic


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Cadherins mediate homophilicadhesion:

Cadherins of a specific subtype on one cell will bind cadherins of the same type onanother cell

F i f C dh i


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Functions of CadherinsE-cadherin

Adherin junction in epithelialcells Connect actin to hold cells

together The first cadherin expressed

during mammaliandevelopment Important in compaction

during embryo development

N-cadherin Crucial in later stages of

vertebrate development Its expression related to the

morphogenesis of nerve cells


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Cell Junctions-specialized structures of the plasma membrane at the

point where two cells come together which are specific meansof joining cells in long-term associations to form tissues and organsin multicellular organisms.


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INTEGRATING CELLS INTO TISSUES

CELL -CELL ADHESION PROTEINS BIND EXTRACELLULARLY AND ARE ATTACHED TO INTRACELLULAR ATTACHMENT PROTEINS

MEMBRANE RECEPTORS BIND INTRACELLULARLY TO CYTOSKELETON


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Four Functional Classes of Cell


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Four Functional Classes of Cell Junctions in Animal Tissues:

Anchoring junctions Cell-cell and cell-matrix

Transmit stresses through tethering to cytoskeleton

Occluding junctions Seal gaps between cells to make an impermeable

barrier

Channel-forming junctions (gap junctions) Link cytoplasms of adjacent cells Signal-relaying junctions

Synapses in nervous system, immunological


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Figure . Summary of the various cell

junctions found inanimal cell epithelia.This drawing is basedon epithelial

cells of the smallintestine.

Junctions


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Junctions

Occluding junctions: tight junctions Anchoring junctions Cell-cell Cell-matrix

Actin Filaments: adhesion belts focal contacts Intermediate filament: desmosomes hemidesmosome

Communicating junctions: gap junctions

Organization of Cell junctions in epithelia


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Organization of Cell junctions in epithelia

Relative positions of the junctions are the same in all epithelia

Table 7. Junctions Between Animal Cells


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Type of Junction Function Features IntermembraneSpace

AssociatedStructures

Adhesive junctions

Desmosome

Hemidesmosomes

Adherens junctions

Adhesion belt

Focal contact

Tight junctions

Gap Junction

Cell-Cell adhesion

Cell-basal laminaAdhesion

Cell-cell adhesion

Cell-ECM adhesion

Sealing spacesbetween cells

Exchange of ionsand moleculesbetween cells

Localized pointsof attachment

Localized pointsof attachment

Continuous

zones of attachmentLocalized pointsof attachmentMembranes

joined alongridgesConnexons(transmembraneproteins with3nm pores)

25-35 nm

25-35 nm

20-25 nm

20-25 nm

None

2-3 nm

Intermediatefilaments(tonofilaments)IntermediateFilaments(tonofilaments)Actin

microfilaments

ActinmicrofilamentsTransmembrane

junctional proteins

Connexons in onemembrane alignwith those inanother to formchannels betweencells


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Anchoring Junctions


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Anchoring Junctions-occur widely in animal tissue but are esp. prominent

In tissues such as heart muscle and skin epithelium that are

Subject to mechanical stress and stretching.*despite structural and functional differences

among them, all adhesive junctions contain 2distinct kinds of proteins:

1. intracellular attachment proteins-link the junctionsto the appropriate cytoskeletal filaments on the inside of the plasma membrane

2. transmembrane linker proteins-protrude on theouter surface of the membrane and bind cells to each otheror to ECM

Cell-Cell Junctions


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Cell Cell JunctionsDesmosomes

Buttonlike points of intercellular contact that rivet cells

together Desmosome are adhesion plaques attached by cadherin-

like transmembrane linker proteins Connect indirectly the intermediate filaments of adjacent

cells to form a continuous network throughout the tissue.Desmosomes attachmuscle cells to eachother in a muscle. Some"muscle tears"involve the rupture of desmosomes

Hemidesmosomes


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Hemidesmosomes Connect the basal

surface of epithelialcells to the underlyingbasal lamina- a

specialized mat of ECM at the interfacebetween theepithelium andconnective tissue.

Adherens Junctions


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Adherens Junctions-prominent in heart muscle and in the thin layers of tissue that line body cavitiesand cover body organs1. Adhesion belt found in epithelial cells which is continuous and form an exten-

sive zone that completely encompass entire cells in a sheet of tissue2. Focal contact also known as focal adhesion

- can attach cells to the ECM

Occluding junction (Tight Junction)


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Occluding junction (Tight Junction)Cell-cell contactTight junctions in vertebrateSeptate junctions in invertebratesEpithelial cells line all the cavities

and free surfaces of bodyThe spaces between epithelial cells

are tightly sealed separating fluids at either

side that have a differentchemical compositions

A selective permeability barrier

specific membrane-boundtransport proteins in apicaland basolateral surfaces fornutrients

G J ti


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Gap Junctions

- (also called communicating junctions) provide cytoplasmic

channels from one cell to an adjacent cell and in thisway are similar in their function to the plasmodesmata inplants. Gap junctions consist of membrane proteins thatsurround a pore through which ions, sugars, amino acids, and

other small molecules may pass. Gap junctions arenecessary for communication between cells in many types of tissues, including heart muscle, and in animal embryos.

Cell-Cell Junctions


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Cell Cell JunctionsGap Junctions

Connections at the lateral surfaces of cells that

allow transport of ions and small molecules (aslarge as 1-2 nm) Channels directly link the cytosol of

adjacent cells The extent to which channels are open is

highly regulated (ex. very high calcium ionconc. closes the channels) In neurons, the passage of ions can lead to

propagation of action potentials In smooth muscle, Ca ++ transfer can

induce contraction Passage of cyclic AMP can lead to signal

transduction A hormonal stimulation of one cell can be

passed to neighboring cells.


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Connexons


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Connexons-at a gap junction, the two plasma membranes from adjacent cells are

joined by tightly packed, hollow cylinders.

6 connexin subunits 2 connexon (one

from each cell) form achannel

Each connexincrosses themembrane four times

Different connexinsform junctions thatdiffer in channel sizeand reguation

Hetero-oligomericconnexons can formhetertypic gap junction channels

Plants


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cell walls are perforated with channelscalled plasmodesmata

Plants


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extracellular matrix (edited)

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