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BMS > The Extracellular Matrix in health and Disease > Flashcards

The Extracellular Matrix in health and Disease Flashcards

1
Q

What are the four macromolecular components of the extracellular matrix?

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

What are the two major structural proteins?

A
  1. ) Collagen (imparts strength)

2. ) Elastin (imparts resilience)

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3
Q

Complex sugars that bind water and resist compression

A

Glycosaminoglycans (GAG)

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4
Q

Proteins with covalently coupled GAG chain

A

Proteoglycans

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5
Q

What are the major adhesive glycoproteins?

A

Fibronectin, laminin, and entactin

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6
Q

These macromolecules along with water and ions are termed the

A

Ground substance

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7
Q

The ground substance plus cells is termed the

A

Connective tissue

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8
Q

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

-Sheets of exctracellulr matrix (ECM) that separate cells

A

Basememnt membranes

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9
Q

If the epithelium is specialized, the basement membrane is called

A

Parenchyma

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10
Q

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

A

Basement membranes

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11
Q

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?

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

-in order of top to bottom

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12
Q

Contains laminin, perlecan, nidogen, and type IV collagen

A

Lamina Densa

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13
Q

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

A

Lamina rara (lamina lucida)

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14
Q

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

A

Lamina Reticularis

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15
Q

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

A

Stroma

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16
Q

In adults, different tissues have quite different stromal

A

Matrix organization

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17
Q

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

A

Tendon stroma

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18
Q

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

A

Cartilage stroma

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19
Q

Has little matrix at all

A

Liver stroma

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20
Q

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

A

Stroma (Bowman’s layer)

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21
Q

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

A

Syndecans and Integrins

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22
Q

It is important that structures are interconnected to maintain

A

Tissue integrity

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23
Q

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

A

Basement membrane

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24
Q

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

A
  1. ) Basal lamina

2. Reticular lamina

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25
Q

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

A

Stroma

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26
Q

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

A

Stroma

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27
Q

A triple-helix protein that provides tensile strength

-25% of total protein

A

Collagen

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28
Q

Colagen is resistant to

A

Stretching

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29
Q

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

A

Fibrils/fibers

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30
Q

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

A

Integrins and Syndecans

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31
Q

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

A

Integrins

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32
Q

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

A

Syndecans

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33
Q

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

A

Collagens

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34
Q

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

A

Glycine

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35
Q

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

A

Helix stability

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36
Q

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

A

Heterogeneity

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37
Q

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

A

Collagen fibers

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38
Q

Leads to the extensive striation pattern seen at the EM level

A

Collagen fiber formation

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39
Q

90% of collagens are

A

Fibril forming Collagen I

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40
Q

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

A

Structure

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41
Q

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

A
  1. ) Fibril forming
  2. ) Fibril-associated
  3. ) Non-fibrillar
  4. ) Transmembrane
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42
Q

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

A

Type I (a fibril-forming) Collagen

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43
Q

Mutations in type I collagen leads to

A

Osteogenesis imperfecta or osteoporosis

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44
Q

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

A

Chondrodysplasia

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45
Q

Widely distributed in the skin and aorta-“reticular” collgen

-Stained with silved

A

Type III collgen

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46
Q

Mutations in type III collagen cause

A

Type III Ehler’s-Danlos-Type 3

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47
Q

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

A

Hyperextended skin and susceptibility to anneurism

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48
Q

Types I, II, and III collagen are all

A

Fibril-forming

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49
Q

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

A

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

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50
Q

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

A

Type IV and Type VII

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51
Q

Located in the basal lamina of basement membranes

A

Type IV collagen

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52
Q

Anchors fibrils at epithelia connective tissue junctions

A

Type VII collagens

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53
Q

Transmembran collagen that connects basement membrane to epithelium via anchoring filaments

A

Type XVII collagen

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54
Q

Epidermolysis bullousa is a disease associated with

A

Type VII collagen

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55
Q

In collagen synthesis, the α chains are synthesized as

A

Pro-α-chains on RER-attached polysomes

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56
Q

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

A

Hydroxylated

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57
Q

Mutations in the collagen hydroxylases alter

A

Collagen assembly

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58
Q

Required for helix stability at physiological temperature

A

Hydroxylation of Proline

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59
Q

Required for intermolecular cross-links to form

A

Hydroxylation of lysine

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60
Q

Required as a co-factor for the collagen hydroxylases

-deficiency causes scurvy

A

Vitamin C

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61
Q

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

A

Degraded

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62
Q

Once hydroxylation has occure, the hydroxylysines are

A

Glycosylated

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63
Q

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

A

Helix formation

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64
Q

Helix formation begins in the ER and goes in the

A

C- to N-terminal direction

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65
Q

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

A

Helix

66
Q

Required for stability of the helix at 37 degrees celcius

A

4’OH-Pro

67
Q

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

A

Hydrogen binding

68
Q

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

A

Extension peptides

69
Q

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

A

Cross-linking

70
Q

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

A

Tropocollagen

71
Q

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

A

Procollagen peptidases

72
Q

Tropocollagen first assembles into a microfibril and then into a

A

Fibril

73
Q

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

A

Head to tail

74
Q

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

A

67 nm

75
Q

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

A

Type III (“Reticular”) collagen

76
Q

Covalent cross-linking of fibrils is catalyzed by

-Cu dependent

A

Lysyl oxidase

77
Q

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

A

Hinge

78
Q

The extension peptides are generally retained in

A

Type IX collagen

79
Q

Functionally imortant for joint integrity

-Mutations cause epiphyseal dysplasia (leads to arthritis)

A

Type IX collagen

80
Q

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

-has multiple regions where the triple helix is interrupted

A

Type IV collagen

81
Q

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

A

Type IV collagen

82
Q

The extension peptides of type IV collagen are not

A

Cleaved

83
Q

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

A

“Chicken-wire” array

84
Q

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

A

Type VII collagen

85
Q

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

A

Lamina densa and anchoring plaque of stroma

86
Q

Absence of type IV collagen leads to

-stroma peels from basement membrane

A

Blistering

87
Q

Attaches basement membrane to epithelial surface via anchoring filaments

-mutation leads to blistering

A

Type XVII collagen

88
Q

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

A

Blistering

89
Q

If VII is mutated, the blistering occurs

A

Below lamina densa

90
Q

If type XVII is mutated, the blistering occurs

A

Above lamina densa

91
Q

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

A

Blistering

92
Q

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

A

Elastin

93
Q

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

A

Aorta

94
Q

Like collagen, elastin is assembled

A

Extracellularly

95
Q

Elastin monomers are highly cross-linked via

A

Unique amino acids

96
Q

What are the two major molecular components in elastic fibers?

A

Cross-linked elastin monomers and fibrillin

97
Q

Participates in the cross-linking of elastin

A

Fibrilin

98
Q

The importance of fibrillin has been seen in

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

A

Marfan syndrom

99
Q

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

A

Aorta

100
Q

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

A

Fibrillin

101
Q

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

A

Glycosaminoglycans

102
Q

The most important glycosaminoglycans (GAGs) are

A

Hyaluronic acid, chondroitin sulfate, and heparan

sulfate

103
Q

All classes of GAGs are sulfated on an amino sugar except

A

Hyaluronic acid

104
Q

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

A

GAG chains

105
Q

GAG chains have a highly extended

A

Random coil

106
Q

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

A

“Sieving”

107
Q

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

A

Lysosomal storage diseases

108
Q

Lethal conditions result from accumulation in lysosome

of iduronic acid from dermatan sulfate and heparan sulfate in

A

Hurler’s syndrome

109
Q

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

-again, hyaluronic acid is an acception

A

Proteoglycans

110
Q

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

A

Epidermolys Bullosa

111
Q

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

A

Aggrecan

112
Q

Membrane associated proteoglycans

A

Heparin Sulfate (HS) proteoglycans

113
Q

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

A

Syndecan family

114
Q

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

A

Syndecans

115
Q

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

A

Mitogenic activity

116
Q

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

A

Perlecan

117
Q

Located in the lamina densa of basement membranes

A

Perlecan

118
Q

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

A

Internal signaling pathways

119
Q

What are three matrix glycoproteins?

A
  1. ) Fibronectin
  2. ) Laminin
  3. ) Nidogen (enactin)
120
Q

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

A

Fibronectin

121
Q

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

A

Wound healing

122
Q

Fibronectin can exist as oligamers attached to the

A

Cell surface

123
Q

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

A

Stroma

124
Q

Synthesized, secreted and bound to fibroblasts and other cell types

-Initially inversely correlated with tumor formation and altered growth

A

Insoluble form of fibronectin

125
Q

Cells lacking fibronectin would lose adhesiveness, round up, and

A

divide

126
Q

An important feature of fibronectin is its

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

A

Modular organization

127
Q

Fibronectin has two binding sites for

A

Integrins, collagen, heparin, and fibrin

128
Q

Produced by hepatocytes and secreted into the bloodstream

A

Plasma fibronectin

129
Q

Produced by fibroblasts and forms part of the extracellular matrix

A

Cellular fibronectin

130
Q

Can bind to both collagen and laminin

A

Integrins

131
Q

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

A

Laminins

132
Q

Laminins generally promote

A

Adhesion

133
Q

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

A

Laminin 1

134
Q

Fibronectin and laminin bind to integrins through

A

RGD

135
Q

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

A

Nidogen (enactin)

136
Q

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

A
  1. ) Syndecans

2. ) Integrins

137
Q

Integrins are dimers composed of

A

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

subunits (8 different types)

138
Q

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

A

Integrin

139
Q

Important amino acid sequence for many integrin binding interactions

A

RGD

140
Q

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

A

Integrins

141
Q

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

A

Focal adhesion kinase (FAK)

142
Q

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

A

Integrins

143
Q

Links fibronectin to actin filaments probably through talin

A

Integrin α5/β1

144
Q

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

A

Paxilin and FAK

145
Q

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

A

Integrin α6/β1

146
Q

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

A

Integrin α6/β4

147
Q

Both integrin subunits are involved in binding substrate via

A

RGD sequence

148
Q

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

A

β-subuint of integrin

149
Q

Bind the actin cytoskeleton and organize signaling molecules

A

Integrins

150
Q

After binding substrate, integrins

A

Cluster

151
Q

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

A

Rho GTPase

152
Q

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

A

Glanzmann’s disease

153
Q

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

-prevents binding of white cells to endothelium

A

Leukocyte adhesion deficiency

154
Q

Cell membrane proteins that both interact with ECM components

A

Integrins and Syndecans

155
Q

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

A

Lymphocyte binding to endothelium via selectin

156
Q

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

A

Leukocyte adhesion to endothelium

157
Q

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

A

Erroneous clotting

158
Q

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

A

Regulation of integrin affinity

159
Q

Regulation of integrin activation is especially important for

A

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

160
Q

What do the following integrins bind and where are they found?

  1. ) Integrin α6/β4
  2. ) Integrin α2/β3
A
  1. ) Laminin, Hemidesmosomes

2. ) Fibrinogen, Platelets

161
Q

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

A

Integrin αL/β2

BMS (62 decks)

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