The Extracellular Matrix in health and Disease Flashcards Preview

BMS > The Extracellular Matrix in health and Disease > Flashcards

Flashcards in The Extracellular Matrix in health and Disease Deck (161):
1

What are the four macromolecular components of the extracellular matrix?

1.) Structural proteins
2.) Glycosaminoglycans
3.) Proteoglycans
4.) Adhesive glycoproteins

2

What are the two major structural proteins?

1.) Collagen (imparts strength)
2.) Elastin (imparts resilience)

3

Complex sugars that bind water and resist compression

Glycosaminoglycans (GAG)

4

Proteins with covalently coupled GAG chain

Proteoglycans

5

What are the major adhesive glycoproteins?

Fibronectin, laminin, and entactin

6

These macromolecules along with water and ions are termed the

Ground substance

7

The ground substance plus cells is termed the

Connective tissue

8

The basal surfce of the epithelium of most tissues is underlain with

-Sheets of exctracellulr matrix (ECM) that separate cells

Basememnt membranes

9

If the epithelium is specialized, the basement membrane is called

Parenchyma

10

Especially abundant under epithelial cells but also surround all endothelial cells and many mesenchymal cells

Basement membranes

11

There are three “layers” of basement membrane that can be defined at EM level that are enriched in specific ECM components. What are the three layers?

1.) Lamina rara
2.) Lamina densa
3.) Lamina reticularis

-in order of top to bottom

12

Contains laminin, perlecan, nidogen, and type IV collagen

Lamina Densa

13

Contains some fibronectin and specific laminin (type 5(, and type XVII collagen from the cell membrane

Lamina rara (lamina lucida)

14

Contains types I, III, and IV collagen, several proteoglycans, and fibronectin

Lamina Reticularis

15

Major component of adult ECM that is located outside the lamina reticularis of basement membrane that is secreted by fibroblasts and specialized mesenchymal cells

Stroma

16

In adults, different tissues have quite different stromal

Matrix organization

17

Has a dense extracellular compartment and is primarily made up of collagen

Tendon stroma

18

MAde up of specific collagens (type II and IX) and the proteoglycan aggrecan

Cartilage stroma

19

Has little matrix at all

Liver stroma

20

Fibronectin, collagen types I, III, VII as well as elastic fibers are in the

Stroma (Bowman's layer)

21

The continuum between the cell surface and the extracellular matrix is mediated by

Syndecans and Integrins

22

It is important that structures are interconnected to maintain

Tissue integrity

23

An extracellular component in direct contact with the basal domain of epithelial cells

Basement membrane

24

At the EM level, the basement membrane is defined by which two layers?

1.) Basal lamina
2. Reticular lamina

25

In some cells, specialized fibroblasts such as chondrocytes or osteoblasts secrete the

Stroma

26

Has few cells, lots of matrix, and dense irregular connective tissue

Stroma

27

A triple-helix protein that provides tensile strength

-25% of total protein

Collagen

28

Colagen is resistant to

Stretching

29

In fibril forming collagens, many triple helical structures will assemble into

Fibrils/fibers

30

There is a continuum between the cell surface and ECM mediated by

Integrins and Syndecans

31

Cell type-specific integral membrane proteins that serve as receptors for components such as fibronectin, laminin, and several collagen types and connect ECM with intracellular signaling pathways and the cytoskeleton

Integrins

32

Specific heparin-sulfate containing proteoglycans that span the cell membrane and interact with actin filaments

Syndecans

33

Triple-stranded helical molecules containing three monomer α-chains wrapped around each other that imparts strength to the molecule

Collagens

34

A unique aspect of the α-chain amino acid composition of collagen is that every third amino acid is

Glycine

35

Between the glycines in the form G-X-Y-G, we often see Proline, lysine, and hydroxylated forms of these amino acids, which contribute to

Helix stability

36

The extend of post translational modification to the collagen aminos can generate

Heterogeneity

37

Assembled extracellularly with many collagen molecules cross-linked and aligned for maximal stability and strength

Collagen fibers

38

Leads to the extensive striation pattern seen at the EM level

Collagen fiber formation

39

90% of collagens are

Fibril forming Collagen I

40

A single glycine mutation in the primary structure of a collagen helix can alter the entire

Structure

41

The number of collagen types has expanded and now totals 20, which can be classified into what 4 major categories?

1.) Fibril forming
2.) Fibril-associated
3.) Non-fibrillar
4.) Transmembrane

42

Most abundant in the tendons, bones, lungs, and skin (represents 90% of all collagen)

Type I (a fibril-forming) Collagen

43

Mutations in type I collagen leads to

Osteogenesis imperfecta or osteoporosis

44

Type II collagen is found in cartilage and makes up 50% of cartilage dry weight. Mutations in type II lead to

Chondrodysplasia

45

Widely distributed in the skin and aorta-"reticular" collgen

-Stained with silved

Type III collgen

46

Mutations in type III collagen cause

Type III Ehler's-Danlos-Type 3

47

Type III Ehler's-Danlos-Type 3 is characterized by

Hyperextended skin and susceptibility to anneurism

48

Types I, II, and III collagen are all

Fibril-forming

49

Type IX collagen, found in the cartilage where it decorates the outside of type II collagen fibers is an example of a

Fibril-associate collagen w/ interrupted triple helix (FACIT)

50

What are the two non-fibrillar (network forming) collagens

Type IV and Type VII

51

Located in the basal lamina of basement membranes

Type IV collagen

52

Anchors fibrils at epithelia connective tissue junctions

Type VII collagens

53

Transmembran collagen that connects basement membrane to epithelium via anchoring filaments

Type XVII collagen

54

Epidermolysis bullousa is a disease associated with

Type VII collagen

55

In collagen synthesis, the α chains are synthesized as

Pro-α-chains on RER-attached polysomes

56

In collagen biosynthesis, the signal peptide is removed. Then proline and lysine are

Hydroxylated

57

Mutations in the collagen hydroxylases alter

Collagen assembly

58

Required for helix stability at physiological temperature

Hydroxylation of Proline

59

Required for intermolecular cross-links to form

Hydroxylation of lysine

60

Required as a co-factor for the collagen hydroxylases

-deficiency causes scurvy

Vitamin C

61

If there is a vitamin C deficiency, hydroxylation does not occur and collagen α chains are

Degraded

62

Once hydroxylation has occure, the hydroxylysines are

Glycosylated

63

Next, N- and C-terminal extension containing cys-rich globular domains (non-Gly-X-Y) guide

Helix formation

64

Helix formation begins in the ER and goes in the

C- to N-terminal direction

65

Formation of hydrogen bonds between Pro and NH2 of Gly to COOH- groups on separate chains leads to formation of

Helix

66

Required for stability of the helix at 37 degrees celcius

4'OH-Pro

67

In one form of osteogenesis imperfecta, helix formation is disrupted by a single Gly to Cys substitution that alters

Hydrogen binding

68

Have low Gly, Pro, OH-Pro and do not form helix. Thus their presence prevents fibril formation within cells

Extension peptides

69

During secretion, extension peptides of fibril-forming collagen molecules (types I, II, III) are cleaved by two procollagen peptidases specific for N- and C-ends leaving a bit of globular domain which participates in

Cross-linking

70

After the extension peptides are cleaved (occurs outside of the cell), the resulting collagen molecules are termed

Tropocollagen

71

Fibril assembly from triple helical molecules can not occur if we are missing

Procollagen peptidases

72

Tropocollagen first assembles into a microfibril and then into a

Fibril

73

Microfibrils aligned with 35 nm overlap between tropocollagen molecules, which are aligned

Head to tail

74

The maximum number of possible inter-chain electrostatic and hydrophobic bonds are formed
when chains are displaced by multiples of

-leads to striated pattern seen in EM

67 nm

75

Stain silver because they have more carbohydrate and thinner fibrils, are more branched, and have fewer bundles

Type III ("Reticular") collagen

76

Covalent cross-linking of fibrils is catalyzed by

-Cu dependent

Lysyl oxidase

77

Type IX collagen, a fibril associated collagen, is less rigid and forms a

Hinge

78

The extension peptides are generally retained in

Type IX collagen

79

Functionally imortant for joint integrity

-Mutations cause epiphyseal dysplasia (leads to arthritis)

Type IX collagen

80

Major collagen of the basal lamina, more specifically the lamina densa

-has multiple regions where the triple helix is interrupted

Type IV collagen

81

Has little extracellular processing of procollagen chains. So, unlike fibrillar collagens, retains globular non-collagen-like extensions at both ends

Type IV collagen

82

The extension peptides of type IV collagen are not

Cleaved

83

Both the C- and N-termini of type IV collagen react to form dimers and tetramers respectively. This results in a

"Chicken-wire" array

84

Contain dimers that form networks of anchoring fibrils that connect lamina densa with matrix components in reticularis or stroma

Type VII collagen

85

In type IV collagen, the C-termini of monomers interact with eachother via disulfide bonds to form dimers, while the N-termini attach to the

Lamina densa and anchoring plaque of stroma

86

Absence of type IV collagen leads to

-stroma peels from basement membrane

Blistering

87

Attaches basement membrane to epithelial surface via anchoring filaments

-mutation leads to blistering

Type XVII collagen

88

If either type VII or type XVII are mutated, the result is

Blistering

89

If VII is mutated, the blistering occurs

Below lamina densa

90

If type XVII is mutated, the blistering occurs

Above lamina densa

91

Mutants with shortened C-termini cannot associate, which results is

Blistering

92

Structural component of ECM that allow stretching and recoil of connective tissues

Elastin

93

One tissue with high elastic fiber (elastin) content is the

Aorta

94

Like collagen, elastin is assembled

Extracellularly

95

Elastin monomers are highly cross-linked via

Unique amino acids

96

What are the two major molecular components in elastic fibers?

Cross-linked elastin monomers and fibrillin

97

Participates in the cross-linking of elastin

Fibrilin

98

The importance of fibrillin has been seen in

-results from missense mutations in the structural gene encoding fibrillin 1

Marfan syndrom

99

Marfan syndrome results from missense mutations in the structural gene encoding fibrillin 1 and leads to elongated extremities and enhanced rupture of the

Aorta

100

At the histological level, elastin can be visualized by the orcein stain, while at EM level, mature elastin molecules are generally surrounded by

Fibrillin

101

Long, unbranched polysaccharide chains consisting of repeating disaccharides that are distinct in different classes but contain alternating amino sugar and uronic acid

Glycosaminoglycans

102

The most important glycosaminoglycans (GAGs) are

Hyaluronic acid, chondroitin sulfate, and heparan
sulfate

103

All classes of GAGs are sulfated on an amino sugar except

Hyaluronic acid

104

Are inflexible with a negative charge that binds water and osmotically active cations

GAG chains

105

GAG chains have a highly extended

Random coil

106

As a result GAG occupy huge space; ECM with high GAG content has the consistency of a hydrated gel and can resist compression and participate in

"Sieving"

107

There are major clinical deficits if normal catabolism of GAG is not maintained. This is seen clearly in

Lysosomal storage diseases

108

Lethal conditions result from accumulation in lysosome
of iduronic acid from dermatan sulfate and heparan sulfate in

Hurler's syndrome

109

Most GAG classes are covalently coupled to "core" protein and thus termed

-again, hyaluronic acid is an acception

Proteoglycans

110

Epithelium and Basement Membrane
peeled away and type VII anchoring
fibrils are disrupted in

Epidermolys Bullosa

111

The prototype proteoglycan is the proteoglycan from cartilage that is 90-95% carbohydrate and is now termed

Aggrecan

112

Membrane associated proteoglycans

Heparin Sulfate (HS) proteoglycans

113

Some heparan sulfate-containing-PGs are integral
membrane proteins with membrane spanning domains in addition to extracellular attachment sites for HS chains. These include members of the

Syndecan family

114

These heparan sulfate
PGs can bind a wide array of molecules including both other matrix components and growth
factors.

Syndecans

115

The binding of one specific growth factor, fibroblast growth factor (FGF) to syndecan is required to maximize

Mitogenic activity

116

There are also additional heparin sulfate proteoglycans that are completely extracellular, such as

Perlecan

117

Located in the lamina densa of basement membranes

Perlecan

118

The interaction of syndecan w/ the cytoskeleton illustrates one connection between ECM and

Internal signaling pathways

119

What are three matrix glycoproteins?

1.) Fibronectin
2.) Laminin
3.) Nidogen (enactin)

120

A glycoprotein formed by two identical chains joined by disulfide linkages close to the C-termini

Fibronectin

121

Fibronectin can exist in a soluble dimeric form that circulates in serum and is involved in

Wound healing

122

Fibronectin can exist as oligamers attached to the

Cell surface

123

Fibronectin can exist as fibronectin fibrils that form an insoluble matrix in the

Stroma

124

Synthesized, secreted and bound to fibroblasts and other cell types

-Initially inversely correlated with tumor formation and altered growth

Insoluble form of fibronectin

125

Cells lacking fibronectin would lose adhesiveness, round up, and

divide

126

An important feature of fibronectin is its

-allows interconnection between series of cell-matrix components at the surface and in the matrix

Modular organization

127

Fibronectin has two binding sites for

Integrins, collagen, heparin, and fibrin

128

Produced by hepatocytes and secreted into the bloodstream

Plasma fibronectin

129

Produced by fibroblasts and forms part of the extracellular matrix

Cellular fibronectin

130

Can bind to both collagen and laminin

Integrins

131

Made up of three major subunits (α, β1, β2) arranged in pattern containing one long arm and three short arms; multiple additional forms have been identified

Laminins

132

Laminins generally promote

Adhesion

133

Located in high abundance in the lamina densa and mediates interactions between cell surface and basement membrane

-has a high affinity for type IV collagen and the HSPG perlecan

Laminin 1

134

Fibronectin and laminin bind to integrins through

RGD

135

Dumbbell shaped structure that binds to laminin 1 and type IV collagen and mediates their interaction with the lamina densa

Nidogen (enactin)

136

What are two major membrane-spanning molecules that serve as receptors for ECM components

1.) Syndecans
2.) Integrins

137

Integrins are dimers composed of

α subunits (18 different types isolated so far) and β
subunits (8 different types)

138

Extracellular laminin, fibronectin, collagen and numerous other cell adhesion molecules all bind

Integrin

139

Important amino acid sequence for many integrin binding interactions

RGD

140

Found on epithelial and mesenchymal cell surfaces and also found on some circulating blood cells

Integrins

141

Once binding to the matrix or other cells has occurred, integrins regulate the activity of kinases such as the

-allows several intracellulr signaling pathways to assemble

Focal adhesion kinase (FAK)

142

Also bind cytoskeletal-associated proteins and thus serve to link
the ECM and cytoskeleton

Integrins

143

Links fibronectin to actin filaments probably through talin

Integrin α5/β1

144

Integrin α5/β1 is a co-receptor with other receptors that lead to phosphorylation of

Paxilin and FAK

145

Major receptor for laminin and may be altered in some forms of muscular dystrophy

Integrin α6/β1

146

Part of hemidesmosome and anchors intermediate (keratin), not actin filaments

Integrin α6/β4

147

Both integrin subunits are involved in binding substrate via

RGD sequence

148

Binds cytoskeleton (often actin) that can initiate formation of signaling complexes

β-subuint of integrin

149

Bind the actin cytoskeleton and organize signaling molecules

Integrins

150

After binding substrate, integrins

Cluster

151

A focal adhesion forms at the site of actin bound integrin via

Rho GTPase

152

One subfamily of integrin receptors (β3), is found on platelets and binds fibrinogen during clotting. Mutations in β3 result in

Glanzmann's disease

153

Another subfamily (β2) is found on white blood cells. Deficiency of β2 results in

-prevents binding of white cells to endothelium

Leukocyte adhesion deficiency

154

Cell membrane proteins that both interact with ECM components

Integrins and Syndecans

155

Changes β2 integrin conformation to allow its binding to endothelial surface receptors

Lymphocyte binding to endothelium via selectin

156

Initial interaction with endothelium is through a different low affinity receptor (selectin). Intracelluar signaling alters integrin conformation which then allows specific, high affinity binding to endothelium and ultimately leukocyte infiltration from blood into the tissue. This describes

Leukocyte adhesion to endothelium

157

Regulation of platelet activation is critical because if platelets aggregated randomly, this would lead to

Erroneous clotting

158

Ensures that binding to integrin occurs only in appropriate environment when clotting is needed

Regulation of integrin affinity

159

Regulation of integrin activation is especially important for

lymphocyte binding to endothelium (β2) and platelet binding to fibrinogen (β3)

160

What do the following integrins bind and where are they found?
1.) Integrin α6/β4
2.) Integrin α2/β3

1.) Laminin, Hemidesmosomes
2.) Fibrinogen, Platelets

161

Found on white blood cells and help mediate attachment to epithelial cells and subsequent movement of WBC into tissue

Integrin αL/β2

Decks in BMS Class (62):