Extracellular MatrixExtracellular Matrix

Readings and ObjectivesReadings and Objectives

• ReadingReading

– Cooper: Chapter 14

• TopicsTopics

• The Extracellular Matrix

• Composition

• Cell-Matrix Interactions

• Cell-Cell Interactions2

Extracellular MatrixExtracellular MatrixIntroductionIntroduction• Cell walls: bacteria, fungi, algae, and higher

plants• Animal cell in tissues embedded in an

extracellular matrix of proteins and polysaccharides

Function• Provides structural support to cells and tissues• Important role in regulating cell behavior

– Cell to cell interaction, communication3

General Structure of Extracellular MatrixGeneral Structure of Extracellular Matrix• Animal cells embedded in an

extracellular matrix• Basal laminae: thin layer on which

epithelial cells rest. Also surrounds muscle cells, adipose cells, and peripheral nerves

• most abundant in connective tissues

• Connective tissue– loose connective tissue– Bone – tendon– cartilage 4

Composition of Extracellular MatrixComposition of Extracellular Matrix

• Fibrous proteins• Polysaccharides- gel like environment• Adhesion proteins- link components of the

matrix to one another and to cells• Different matrices have different amounts of

each component– Tendons, rich in fibrous proteins– Cartilage, high in polysaccharides– Bone, calcium phosphate crystal deposition

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• Collagen- major structural fibrous protein

• Forms triple helices• Triple helix domains: repeats of the

amino acid sequence Gly-X-Y• Glycine in every 3rd position• X=Pro, packs helices closely• Y= hydroxyproline,

synthesized in ER• Pro, Hpro stabilizes

by helping H-bonding

Matrix composition: Collagen

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• Type I collagen- the most abundant• polypeptide chains have about 330

Gly-X-Y repeats• Secreted through ER/golgi, form

collagen fibrils • Triple helical molecules are

associated in regular staggered arrays

• Covalent cross-links: lysine and hydroxylysine side chains

• strengthen the fibrils• Fibrils form collagen fibers, several

µm in diameter

Matrix composition: Collagen

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• Some are not fibril forming• Fibril-associated collagens: bind to

collagen fibrils, link to others or to other matrix components

• Network-forming collagens: have non helical interruption, cross-link to network

• Anchoring fibrils: link basal laminae to underlying connective tissues

• Transmembrane collagens: proteins that participate in cell-matrix interactions

Types of Collagen

8Network-forming collagens

• Extracellular matrix gels are polysaccharides called glycosaminoglycans (GAGs).

• GAGs are repeating units of disaccharides: One sugar is either N-acetylglucosamine or N-acetylgalactosamine, the second is usually acidic (glucuronic acid or iduronic acid).

Matrix Polysaccharides

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• sulfate groups make GAGs negatively charged

• bind positively charged ions and trap water molecules to form hydrated gel

• GAGs are linked to proteins to form proteoglycans

Matrix Polysaccharides

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• Link matrix components– to each other– to cell surfaces

• Fibronectin : main adhesion protein of connective tissues

• A homodimeric protein (2500 aa/subunit), binds – collagen and GAGs– cells

• Recognized by cell surface receptors • Attachment of cells to the

extracellular matrix

Matrix Adhesion proteins: Fibronectin

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• Laminin: adehsion protein of basal laminae

• Heterotrimeric: α, β, and γ-chains(5, 4, 3 genes, respectively)

• have binding sites for– cell surface receptors, eg integrins– type IV collagen– Proteoglycans

• Assemble to cross-linked network

• Linking cells and matrix

Matrix Adhesion proteins: Laminins

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Cell-Matrix InteractionsCell-Matrix Interactions• Integrins: major cell surface

receptors, involved in attachment of cells to the extracellular matrix

• Transmembrane proteins, heterodimer of α and β subunits (18α, 8β)

• Bind to short aa in,– Collagen– Fibronectin– laminin

• also anchor the cytoskeleton to the extracellular matrix

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Cell-Matrix JunctionsCell-Matrix JunctionsTwo types of cell-matrix junction• Focal adhesions: bundles of actin

filaments are anchored to β subunits of integrins via

– α-actinin– Vinculin via talin

• Assembly of focal adhesions• Focal complex: small group of

integrins• Recruite Talin, Vinculin, α-actinin

and Formin• Formin initiates actin bundles

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Focal adhesions are reversibleFocal adhesions are reversible• Integrins can reversibly bind matrix components• change conformation between active and inactive states• Inactive state: integrin heads turned close to cell surface• Cell signaling extends heads to matrix• Migrating cells: focal adhesions form at the leading edge

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Cell-Matrix Junctions: HemidesmosomesCell-Matrix Junctions: Hemidesmosomes

• Hemidesmosomes anchor epithelial cells to the basal lamina

• α6β4 integrins bind to lamins

• long cytoplasmic tail of β subunit binds to intermediate filaments via

• Plectin and BP230 and BP180 (similar to transmembrane collagens)

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Cell-Cell interactionsCell-Cell interactions• Interactions between cells are critical for development

and function of multicellular organisms• Cell-cell interactions:

– Transient: activation of immune cells; migration to injury site – Stable: role in the organization of tissues.

• Cell-Cell junctions allow rapid communication between cells

• During embryo development, cells from one tissue specifically adhere to cells of the same tissue rather than cells of a different tissue

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Cell-Cell interactionsCell-Cell interactions• Cell-cell adhesion- mediated by four groups of cell

adhesion molecules• Selectins, integrins, the immunoglobulin (Ig) superfamily,

and cadherins• Many adhesions are divalent cation-dependent, requiring

Ca2+, Mg2+ or Mn2+

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SelectinsSelectins• Selectins- transient interactions between leukocytes and endothelial cells• Leukocytes slow down, flattened, migrate from the circulation to sites of tissue inflammation• initial adhesion• stable adhesions

binding of integrinsto intercellular adhesion molecules(ICAMs) on endothelial cells

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Cell to Cell JunctionsCell to Cell Junctions

Four types of Cell-Cell connections in

animal cells

• Adherens Junctions

• Desmosomes

• Tight Junctions

• Gap Junctions

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Adherens JunctionsAdherens Junctions

• Cadherin form stable cell-cell connections involve actin filaments

• Also include β-catenin, p120, and α-catenin,

• β-catenin and p120 bind to cadherin and help maintain stability

• β-catenin binds α-catenin that interacts with actin filament of cytoskeleton

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DesmosomesDesmosomes• link the intermediate

filament of adjacent cells• Desmoglein and

desmocollin (transmembrane cadherins) bind by heterophilic interactions across the junction

• Plakoglobin and plakophilin bind to the cadherins and link to the intermediate filament binding protein, desmoplakin

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Tight JunctionsTight Junctions

• Tight junctions provide minimal adhesive strength between the cells, usually associated with adherens junctions and desmosomes in a junctional complex

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Tight JunctionsTight Junctions• Tight junctions in

epithelial cell form a seal that prevents free passage of molecules and ions between cells

• separate apical and basolateral domains of the plasma membrane

• prevent free diffusion of lipids and membrane proteins 24

Tight JunctionsTight Junctions• transmembrane proteins, occludin,

claudin, and junctional adhesion molecule (JAM), anchored on F-actin

• Bind similar proteins on the adjacent cell• Sealing the space between cells

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Gap JunctionsGap Junctions• open channels through the plasma

membrane• allowing ions and small molecules to

diffuse freely• Proteins and nucleic acids can not

pass through• heart muscle cells, passage of ions

through gap junctions synchronizes the contractions of neighboring cells

• allow passage of some signaling molecules, such as cAMP and Ca2+, coordinating responses of cells in tissues 26

Gap JunctionsGap Junctions• Gap junctions are made of

transmembrane proteins in the connexin family

• 6 connexins form a cylinder with an open aqueous pore in its center, called a connexon

• Connexons in the plasma membrane adjacent cells align

• form open channels between the two cytoplasms 27

Gap JunctionsGap Junctions

• Specialized gap junctions occur on specific nerve cells and form an electrical synapse

• Individual connexons can be opened or closed

• When open, they allow rapid passage of ions between the two nerve cells

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