Lecture 11 - The Extracellular Matrix Flashcards by D B

All multicellular organisms have an

Extracellular matrix

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The ECM supports

Cells

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Different types of ECM control (6)

Cell adhesion
Signalling
Differentiation
Polarity
Division
Migration

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During embryonic development, the ECM is integral to

Migration events that determine body polarity
Differentiation of stem cells
Reservoir of growth factors

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How many types of matrix do animals have

Two

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The interstitial matrix forms

Tissues and gives support to organs

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The basal lamina

Underlies all epithelial cell layers

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The two main macromolecules that form the ECM are

Fibrous proteins (glycoproteins)

2. Polysaccharide chains (glycosaminoglycans)

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What do glycosaminoglycans do

Link to core proteins to form proteoglycans

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Variations in ECM composition cause

Diversity of materials to be formed

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Calcified ECM forms

Bones and teeth

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Soft transparent ECM forms

The cornea

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The interstitial matrix is found in

Connective tissues

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Which cell secretes the interstitial ECM?

Fibroblast cells

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ECM molecules are synthesised

Intracellularly and then excreted by exocytosis

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Once outside the cell, ECM molecules

Aggregate

to form a huge organised matrix

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Chondrocytes form

Cartilage

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Osteoblasts form

Bone

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Collagen provides

Tensile strength in connective tissues

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How many collagen genes do mammals have?

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25% of protein mass in a mammal is

Collagen

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Collagen is a very large macromolecule, so must be secreted in a precursor form called

Procollagen

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Procollagen

Intracellular form of collagen that prevents aggregation

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Procollagen is cleaved outside the cell which allows

Aggregation

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What kind of helix is collagen?

Triple helix

Inside the cell, collagen is a

Triple helix

Outside the cell, collagen assembles into a

Fibril

Collagen fibrils assemble into collagen

Fibres

Collagen fibres lie

Criss crossed to provide strength

Collagen is

Post translationally processed

In the nucleus, collagen is

Transcribed from DNA > RNA > mRNA from the collagen gene

In the RER, collagen is

Translated into pre procollagen

Pre procollagen is labelled on the

N terminus to target it to the secretory pathway

Lysine residues on pre procollagen are

Hydroxylated

Hydroxylation of collagen is necessary for

O linked glycosylation

In the Golgi, pre pro collagen is

Hydroxylated Glycosylated Disulfide bonded

When the collagen leaves the Golgi, it is

Procollagen packed in secretory vesicles

Once outside the cell, procollagen is

Proteolytically cleaved

N proteinase cleaves the

N terminus of procollagen extracellularly

C proteinase cleaves the

C terminus of procollagen extracellularly

N and C proteinase cleavage allow

The higher order assembly of collagen | From fibrils to fibres

Ehlers Danlos disease is a

Genetic disease that affects procollagen or procollagen processing enzymes

In Ehlers Danlos, collagen fibrils do not

Assemble correctly (no criss crossing)

Symptoms of ED (5)

1. Bruising, stretchy skin 2. Dislocation of joints, hyperflexibilty 3. Arterial rupture 4. Scoliosis 5. Thin and fragile globe of eye

ED type 6a has a defect in which gene?

Plod1

Plod genes encode for

Lysyle hydroxylases | add OH to lysine in collagen

Mutation in Plod1 results in

No hydroxylation of lysine in collagen | Therefore no O-linked glycosylation

What resists compression and fills space in the interstitial ECM?

Polysaccharide and protein gels

Proteoglycans are

Extracellular proteins linked to glycosaminoglycans (GAGs)

Proteoglycans can have

Many GAG chains attached to them

Proteoglycans and GAGs can form

Huge macromolecules resembling bottlebrushes

Proteoglycans and GAGs form gels that combine with what to form an interstitial ECM?

Collagen

The basal lamina anchors

Epithelial cells to the tissues underneath

The basal lamina separates

Different connective tissue layers

The basal lamina forms

A mechanical connection between layers of connective tissue

The basal lamina can act as a

Selective filter

In the kidney glomerulus, the basal lamina prevents

Blood and urine mixing

The basal lamina is synthesised by

The cell layers on either side of it

The basal lamina looks like

Mat like sheets

Fibrillar collagen makes up the

Intersitial ECM

Collagen type4 and laminin make up the

Basal lamina

Nidogen and Perlecan

Cross link laminin and collagen type 4 together to hold the basal lamina together

Laminin organises the

Basal sheet

Laminin forms a

Triple helix part opens into 3 separate chains to form a 'cross'

How many laminin isoforms are there?

The most abundant laminin in the body is

Laminin 511

Many different protein isoforms suggest

Tissue specificity

Laminin structure

Alpha, beta and gamma chains disulfide bonded chains Self assembles Long arm binds to cell surface receptors Short arms join to other laminins

Collagen 4 provides

Tensile strength Triple helix Procollagen Self assembles

Why can collagen 4 form a sheet?

Primary amino acid sequence of collagen 4

GlyXY

Interrupted repeats of glycine confers bendiness to form a sheet

Epidermolysis bulleosa is a

Genetic disease that forms blisters on the skin | Caused by failure in adhesion between dermis and epidermis

During cell migration, focal adhesions form

At the cell front and disassemble at the back

Focal adhesions are

Connections between the cell cytoskeleton and the ECM | Have receptors to confer specificity

Focal adhesions provide

``` The force to move the cell Signalling cues (matrix molecules and growth factors) ```

Integrins are

Transmembrane receptors that couple the matrix to the cytoskeleton Binding allows tension generation

Integrin structure

Heterodimer | alpha + beta subunit

Integrins link to actin via

Actin binding proteins (ABPs)

Integrins signal

Mechanically and chemically

Tensin, Talin and Vinculin

Form an adhesion complex with integrin that link the actin cytoskeleton to the ECM in a migrating cell

Mature focal adhesions are

Dynamic multi protein complexes

Integrins can signal

Bidirectionally

When integrin is folded, it is

Inactive (does not bind to ECM or cytoskeleton)

When integrin is unfolded, it is

Active (binds to ECM + cytoskeleton)

Outside-in integrin signalling activates

A protein tyrosine kinase cascade

Integrin signalling impacts (3)

Nuclear functions RhoGTPases Actin cytoskeleton: migration, spreading, polarity

What are neural crest cells?

Cluster of stem cells at the top of the neural tube

Downregulation of N-CAM in neural crest cells results in

A loss of adhesion which allows migration

Neural crest cells differentiate into cell type depending on

The ECM and cell environment

Laminin and Fibronectin

Cause neural crest cells to migrate