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21 fall: Biochem > Test 2 lecture 36-37 > Flashcards

Test 2 lecture 36-37 Flashcards

1
Q

ECM is made of

A
  • *ground substance:**
  • glycoproteins, proteoglycans and glycosamioglycans
  • *Fiber components:**
  • collagen
  • elastin
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2
Q

Collagen breaks into

A

reticular fibers: lungs, kidneys, lymph nodes

fiber forming:

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3
Q

molecules that help ECM

A

integrin: bind ECM components together

Metalloproteinases: enzymes that degrade ECM

Growth factors and cytokines:

Transcription factors

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4
Q

to be a collagen:

A
  1. must be in the extracellular space and contribute to the structural integrity of the ECM;
  2. contain at least one triple-helical domain;
  3. must form supramolecular aggregates (i.e. fibrils (type 1 and 2), filaments (reticular fibers), networks) either alone, or in conjunction with other matrix components.
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5
Q

To be classified as a collagen, the protein must contain at least one ____

A

triple-helical domain;

wrap around each other and form rope like structure

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6
Q

To be classified as a collagen, the protein must be in the extracellular space and contribute to the ____ of the ECM

A

structural integrity

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7
Q

To be classified as a collagen, the protein must form ____ (i.e. fibrils, filaments, networks) either alone, or in conjunction with other matrix components.

A

supramolecular aggregates

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8
Q

type 1 collagen

A

present in bone, and other tissues (DICT, tendons and ligaments)

is a type of fiber forming collagen

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9
Q

type 2 collagen is found in

A

cartilage

type of fiber forming collagen

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10
Q

Collagen superfamily: >28 structurally and functionally distinct collagen types with unique ___ exist.

A

tissue distributions

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11
Q

Some collagen types (e.g. ____) are homotrimers made up of 3 identical polypeptides or alpha “a” chains,

A

type II collagen in cartilage

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12
Q

Some collagen are heterotrimers made up of combinations of 2 or 3 different a chains (____).

A

type I collagen in bone

is a heterotrimer of 2 identical alpha 1 chains, and 1 different alpha2 chain

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13
Q

___ form cross-striated linear fibrils and are major structural components of connective tissues

A

fibrillar collagen

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14
Q

two types of fibrillar collagen

A

Type 1- bone, skin, tendon, dentin, blood vessels, mesenchyme..

Type 2-cartilage, vitreous of eye

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15
Q

type of collagen that forms non-linear aggregates; have varied function

A

non fibrillar collagen

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16
Q

examples of non fibrillar collagen

A
  1. BASEMENT MEMBRANE: Type IV
  2. ANCHORING : Type VII
  3. FACIT : Types IX, XII, XIV
  4. SHORT CHAIN : Types VIII, X
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17
Q

Formula for triple helical domain:

A

(GLY-X-Y)n

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18
Q

collagen alpha chains are coiled around each other into a ___ to form a rigid rope-like structure.

A

triple-helix

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19
Q

___, the smallest amino acid and the only one without a side chain, is critical in every third position of the collagen Gly-X-Y sequence.

A

Glycine

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20
Q

___ residues occupy the restricted space in the center of the triple helix of collagen

A

Glycine

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21
Q

Why can only glycine work in center of triple helix of collagen

A

Any other amino acid in this position disrupts the helix. (would be too big)

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22
Q

In collagen, the side chains in the -X and -Y positions are directed ___, at the surface of the protein, where they participate in intra- and inter-molecular interactions.

A

outward,

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23
Q

____ have large (~1,000 aa’s per chain) triple helical domains with virtually no interruptions or “imperfections” in the Gly-X-Y repeats.

A

-Fibrillar collagens

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24
Q

These collagens form straight rope-like structures and laterally associate into quarter-staggered arrays.

A

Fibrillar collagen

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25
Q

___ have either imperfections and/or large interruptions within the Gly-X-Y repeats.

A

non fibrillar collagen

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26
Q

These type of collagens are often kinked, and form different supramolecular aggregates.

A

non fibrillar collagen

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27
Q

Triple-helix structure and stability depends on ___,___,___ and ___ residues.

A

proline, hydroxyproline, lysine, hydroxylysine

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28
Q

____, are rigid or cyclic amino acids that limit the rotation of the polypeptide backbone, and participate in inter- and intra-chain bonds.

A

proline, hydroxyproline, lysine, hydroxylysine residues

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29
Q

Supramolecular organization of fibrillar collagen

A

quarter-stagger array to form fibrils.

hole zones, visible as bands or cross-striations

Further ordering of fibrils depends upon the strength needed in the tissue. (e.g. In bone, type I collagen fibrils are arranged in layers perpendicular to those in the adjacent layers; in cartilage, type II collagen fibrils randomly criss-cross).

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30
Q

Fibrillar collagen molecules align in a ____ to form fibrils.

A

quarter-stagger array

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31
Q

quarter-stagger array of fibrillar collagen leaves gaps or ___, visible as bands or ____ under an electron microscope.

A

hole zones

cross-striations

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32
Q

mutations in type 9 collagen causes

A

early onset OA

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33
Q

early onset OA is caused by mutations in

A

type 9 collagen

FACITS

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34
Q

How is collagen formed

A
  1. Transcription and translation
  2. Intracellular modifications (cotranslational and post-translational modifications)
  3. Extra Cellular modifications
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35
Q

type of intracellular modifications when making collagen

A
  • *Cotranslational and posttranslational modifying enzymes:**
    1. Removal of signal sequence
  1. Hydroxylation of some pro and lys residues
  2. Glycosylation of some lys residues

In the RER or golgi, the α chains fold into trimers:

-Chain association and disulfide bonding in the carboxyl domain

-Trimerization

-Translocation and secretion of procollagen

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36
Q

extracellular modifications when making collagen

A

Removal of amino (NT) and carboxyl (CT) propeptides (in fibrillar collagens)

Lateral associations into ordered supramolecular aggregates

Intra- and inter-chain lysine-derived cross-link formation

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37
Q

Upon synthesis on membrane-bound ribosomes, each αlpha chain contains a hydrophobic ___ , that is cleaved off the αlpha chains as they enter the rough endoplasmic reticulum (RER).

A

signal peptide

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38
Q

As αlpha chains, enter the rough endoplasmic reticulum (RER) ____ occurs

A

trimerization

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39
Q

After trimerization occurs in the RER, the ___ and ___ are cleaved in the ECM

A

N-terminal propeptide and C-Terminal propeptide

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40
Q

What happens to fibrillar collagen polypeptide when it enters the RER?

A

Removal of signal sequence

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41
Q

Proline (Pro) and Hydroxyproline (Hypro) represent ___ of the triple helix. These cyclic residues provide ___ by limiting rotation of the polypeptide backbone.

A

~30%

structural stability

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42
Q

Hydroxyproline is generated by ____ modification, and is essential for ___.

A

posttranslational

thermal stability

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43
Q

Proline hydroxy groups form ___ which maintain the structure of the triple helix at body temperature.

A

water-bridged hydrogen bonds

44
Q

Trimerization of alpha chains does not occur without ____

A

Hydroxyproline.

45
Q

Hydroxyproline will ___ the melting temperature of collagen

A

increase

Tm (melting temperature) of a polypeptide composed of (Pro-Pro-Gly) repeats is
24°C,

while the Tm of a polypeptide composed of (Pro-Hyp-Gly) is 58°C.

46
Q

___ in the “Y” position are essential for intra-and intermolecular cross-links that stabilize the lateral associations of collagen molecules in fibrils.

A

Hydroxylysines

47
Q

Prolyl and lysyl hydroxylases are enzymes in the ER that ___ selected prolines or lysines while the polypeptide chains are growing.

A

hydroxylate

48
Q

hydroxylation of selected prolines or lysines occurs before or after trimerization of collagen fibers

A

before trimerization

49
Q

___ are enzymes that require ferrous iron and ascorbate cofactors; the ferrous iron is needed at the active site, and is maintained in a reduced state by the reducing agent ascorbate (vitamin C).

A

Prolyl and lysyl hydroxylases:

50
Q

Prolyl and lysyl hydroxylases need __ to work.

A

ferrous iron and ascorbate cofactors

oxygen and aplha-ketoglutarate co-substrates

51
Q

ascorbate is

A

vitamin C

needed for Prolyl and lysyl hydroxylases enzymes

52
Q

ascorbate deficiency

A

scurvy

The forming collagen aplha chains are underhydroxylated and do not form stable helices at body temperature. Supramolecular aggregates are also destabilized due to reduced cross-linking.

53
Q

In scurvy, The forming collagen alpha chains are ___ and do not form stable helices at body temperature. Supramolecular aggregates are also destabilized due to reduced ___ .

A

under hydroxylated

cross-linking

54
Q

make up of a forming collagen alpha chain

A

signal peptide

NT(amino terminal) domain-globular domain

TH domain- (Gly-X-Y)n

CT domain- globular domain

-everything except TH domain gets cut off TH will trimerize

55
Q

Proline hydroxy groups form ___ which maintain the structure of the triple helix at body temperature, ___ melting temperature of alpha helix of collagen

A

water-bridged hydrogen bonds

increase

56
Q

cofactors needed for prolyl hydroxylase and lysyl hydroxylase

A

ascorbate (vit C)

ferrous iron (active site kept in reduced state by vitamin C)

57
Q

Carboxyl (CT) domains of alpha chains are needed for proper chain alignment prior to ___ formation

A

triple helix

58
Q

3 alpha chains are first stabilized by interchain ___ within the CT, followed by a ___ folding of the chains into trimers, starting at the CT domain and proceeding to the amino domain (NT).

A

disulfide bonds

zipper-like

CT to NT back to front

59
Q

Most mutations in the CT domain prevent the mutant alpha chain from participating in chain association, and thus cause a reduction in the amount of trimeric molecules formed, leading to ____

A

“Haploinsufficiency”

60
Q

Trimeric collagens are translocated in secretory vesicles from the ER or golgi to the ___.

A

ECM

61
Q

Removal of amino (NT) and carboxyl (CT) propeptides by N-and C-proteases permits ____ of collagen trimers into fibrils.

A

lateral alignment

62
Q

lateral alignment of collagen trimers into fibrils happens after ___ are removed by ___

A

amino (NT) and carboxyl (CT) propeptides

N-and C-proteases:

63
Q

Defect is a deficiency in N-protease in the skin, resulting in the persistence of the NT domain, common in cattle and sheep- fragile skin and death

A

Dermatosporaxis

64
Q

Dermatosporaxis

A

autosomal recessive birth defect in cattle and sheep

extremely fragile skin and death

deficiency in N-protease in the skin, resulting in the persistence of the NT domain.

Electron microscopy shows branched, twisted collagens that prevent packing of collagen molecules into cylindrical fibrils.

65
Q

NT and CT are removed in the ___

A

ECM,

66
Q

Once NT and CT are removed in the ECM, collagen molecules align ___ in a quarter-stagger to form___.

A

laterally

fibrils

67
Q

Lysines, hydroxylysines and glycosylated lysines are modified by ___ to generate aldehydes that form covalent ___, joining one collagen molecule to the next in the same or another fibril.

A

lysyl oxidase

cross-links

68
Q

lysyl oxidase

A

modify Lysines, hydroxylysines and glycosylated lysines to form aldehydes that form covalent cross-links, joining one collagen molecule to the next in the same or another fibril.

require O2 and copper( in cupric form)

69
Q

Cross-linking ___collagenous aggregates.

A

strengthens

70
Q

Cross-linking defect

A

lathyrism

71
Q

Lathyrism.

A

Cross-linking defects

A. Nutritional: copper deficiency in swine, chicks, sheep leads to blood vessel rupture.

B. Toxic: sweet peas and clover contain β-aminoproprionitrile (BAPN), which binds irreversibly with lysyl oxidase and prevents cross-linking. Collagen is extremely weak, and bones are brittle and misshapen.

72
Q

defect in CT domain disulfide bond formation

A

haploinsufficiency

73
Q

Ascorbate deficiency

A

scurvy

alpha chains under hydroxylated and can not form stable helices at body temperature-

no hydroxylation= no hydrogen bonds holding triple helix in place= kinks

74
Q

issues with removal of NT domain from alpha helix

A

dermatosporaxis

75
Q

disorder with cross linking of triple helix

A

lathyrism

prevents cross linking between triple helix, collagen fibril very brittle and weak

76
Q

BAPN is an inhibitor of

A

lysyl oxidase

prevents cross linking of collagen to produce fibril

77
Q

Supramolecular aggregate formations involving FACIT collagens are (collagen Types I & __) and (collagen types II & __).

A

type 1 (bone) and XII

type 2 (cartilage) and IX

78
Q

two type of type 1 collagen disorders

A

osteogenesis imperfecta

Ehlers danlos VII syndrome

79
Q

osteogenesis imperfecta

A

brittle bones, incomplete mineralization

Other symptoms may include poor or altered mineralization, osteoporosis, joint laxity, blood vessel rupture, blue sclera.

condition: variable: often lethal in utero, severely deforming or barely noticeable

Lethal: caused by glycine not being every 3rd amino acid in TH region, either deleted or substituted

Collagen type: type 1 (alpha 1 and alpha 2)

80
Q

ehlers danlos VII syndrome

A

loose joints and hyperelastic skin

condition: mild to moderate

Type 1 (alpha 1 and alpha 2)

error in the NT domain of collagen alpha helix

81
Q

Type I collagen

A

(fibrillar collagen):

  1. Major protein of the ECM
  2. Found in bones, teeth, tendons, blood vessels
  3. Is a heterotrimer composed of two “α1” and one “α2” chains
  4. Chains associate at the carboxyl domain and fold into triple-helical molecules
  5. Triple-helical molecules self-assemble into fibrils, which provide tensile strength to the tissue, and serve as templates for mineral deposition.
82
Q

Based on location and type of mutation, the severity of the disease can be predicted. Mutations in the ___ usually result in less severe phenotypes than mutations in the ____ domain

A

carboxyl domain

triple-helical

83
Q

Haploinsufficiency

A

mutation in the carboxyl domain

this scenario results in a 50% reduction of trimeric collagens produced.

kinked- ends of alpha chains can not line up- trimerization can not occur

84
Q

Dominant interference

A

results from the expression of partially-functional collagen α chains that are able to compete with normal chains for binding at the carboxyl domain;

following binding, these hybrid molecules cannot form stable trimers.

lead to either a degradation or abnormal molecules interfere with the normal function

In general, mutations resulting in partially-functional molecules give rise to more severe phenotypes than mutations that prohibit the chains from binding prior to trimerization.

85
Q

In general, mutations resulting in partially-functional molecules give rise to ___ phenotypes than mutations that prohibit the chains from binding prior to trimerization.

A

more severe

86
Q

In haploinsufficiency ___ % of trimers are normal and ___ % are degraded

In dominant interference ___ % of trimers are normal , ___% are abnormal and ___ % are degraded

A

50% and 50%

12.5 normal, 12.5 abnormal and 75% degraded

87
Q

Unbranched polysaccharide chains composed of repeating disaccharide units

A

GLYCOSAMINOGLYCANS / “GAGs

88
Q

In GAG, 1 of the 2 sugar residues in the repeating disaccharide is an amino sugar (n- ___or ____); the second sugar is a uronic acid (___ or ___)

A

acetylglucosamine or acetylgalactosamine

glucuronic or iduronic

89
Q

Gags are usually highly negatively charged due to ___ and ___ on the sugar residues;

A

carboxyl

sulfate groups

90
Q

Gags are found in the ___ and on ___

A

ECM

cell surface

91
Q

6 gag groups are distinguished by

A

a) sugar residues
b) type of linkage between these residues
c) number and location of the sulfate groups.

Of these, all but HA are covalently linked to a protein core to form proteoglycans

92
Q

Of the 6 GAG groups all but __ are covalently linked to a protein core to form proteoglycans

A

Hyaluronic acid (HA)

93
Q

IN GAG: ___ bind with glucoronic acid- this is called a ___

and ___ bind with iduronic acid- this is called ___

A

n- acetylglucosamine (hyaluronan)

n-acetylgalactosamine (dermatan sulfate)

94
Q

Hyaluronan is a simple GAG, with a long chain of ~25,000 sugar residues and no ___.

A

sulfate groups

95
Q

Dermatan sulfate GAG has a high density of negative charges due to ___ and ___.

A

both carboxyl and sulfate groups

96
Q

Specific characteristics of each GAG:

Hyaluronic acid (HA):

A

1) simplest GAG
2) least negatively charged (no sulfate groups)
3) highest molecular weight (>10 6 daltons)
4) not made on a protein core

no sulfate group

5) serves as the backbone for the cartilage PG aggrecan.

97
Q

Chondroitin sulfate (CS) and keratan sulfate (KS):

A

1) are highly negatively charged
2) are components of the cartilage PG aggrecan

filled with water, very sponge like- compressive forces

98
Q

Dermatan sulfate (DS)

A

1) is a component of two bone PGs, biglycan and decorin

99
Q

Heparin (HN):

A

1) most negatively charged GAG
2) found in mast cells
3) has anticoagulant and antiproliferative properties
4) most commonly a component of the PG serglycin.

100
Q

Heparan sulfate (HS):

A

1) found on cell surfaces in PGs such as sydecan, glypican, and perlecan
2) proposed to regulate cytokine-mediated cell interactions.

101
Q

6 GAGs

A

Hyaluronic acid (HA):

Chondroitin sulfate (CS)

Keratan sulfate (KS):

Dermatan sulfate (DS):

Heparin (HN)

Heparan sulfate (HS):

102
Q

Linkage between a GAG chain and its core protein in a proteoglycan molecule.

A link tetrasaccharide is first assembled typically on a ___ residue. The rest of the GAG chain, consisting of a repeating disaccharide unit, is then synthesized, with one sugar residue added at a time.

A

serine

103
Q

how to make cartilage proteoglycan (aggrecan) biosynthesis

A

3- protein core of aggrecan.

(4-5) Protein core is transported from RER to golgi.

(6) In golgi, GAG chains are added to the protein core, one sugar at a time.
(7) On completion of glycosylation and sulfation, molecules are transported via secretory vesicles to ECM
(8) . Hyaluronan is made on the plasma membrane
(9) . In the ECM, aggrecan, link protein, and hyaluronan come together to form proteoglycan aggregates

104
Q

lysyl oxidase is dependent on ___, used to form cross links

A

Copper

105
Q

steps to make collagen

A
  1. signal protein cut off
  2. prolyl/lysysl hyrdoxylase and asorbate hydrolyses TH
  3. CT bind together using disulfide bonds
  4. TH trimer formed
  5. secreted into ECM NT and CT cut of (Cross links formed (lysyl oxidase and copper)
106
Q

4 types of mature proteoglycans

A

aggrecan (cartilage- very negative, withstand compression (chondroitin sulfate and karatan sulfate))

decorin (smallest, found in bone, make sure distance between type 1 collagen fibrils stays the same(dermatan sulfate))

Serglycrin - made by mast cells, heparin chains

syndecan- cell membrane proteoglycan, heparan sulfate, cytokine metabolism

107
Q

how to make proteoglycan

A
  1. In RER: protein synthesis (make core protein)
  2. sugars added one at a time to core protein in the golgi
  3. sugars become sulfated in the golgi
  4. when fully made, gets packaged into secretory vesicles and moved to ECM
  5. Hyaluronic acid, made on cell membrane is released into ECM and forms backbone for aggrecan to attach
  6. link proteins bind these together

21 fall: Biochem (44 decks)

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