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BIOCHEMISTRY > WEEK 8 (Collagen and Elastin) > Flashcards

WEEK 8 (Collagen and Elastin) Flashcards

1
Q

What are fibrous proteins usually folded into?

A

Either extended filaments or sheetlike structures with repeated amino acid sequences

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2
Q

What are the characteristics of fibrous proteins?

A
  • relatively insoluble
  • provide structural or protective function in our tissues (connective tissues, tendons, bone, muscle fibers, blood vessel walls, sclera & cornea of eye)
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3
Q

What are the characteristics of Collagen?

A
  • most abundant protein in the human body
  • LONG, RIGID structure in which three polypeptides are wound around one another in a ROPE-LIKE TRIPLE HELIX
  • collagen may be dispersed as a GEL that gives support to the structure (e.g in ECM or the vitreous humor of the eye)
  • collagen may be bundled in TIGHT, PARALLEL fibers that provide great strength (e.g in tendons)
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4
Q

How many collagen types does the collagen superfamily of proteins include?

A

Over 25

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5
Q

What do variations in the amino acid sequence of the alpha chains result in?

A

components that are about the same size but with slightly different properties

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6
Q

What is the difference between the composition of type I and type II collagens?

A

type I contains two chains called alpha-1 and one chain called alpha-2

type II contains three alpha-1 chains

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7
Q

The collagens can be organised into how many groups and based on what?

A

three groups

based on their location and functions in the body

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8
Q

What are the three different groups that collagens can be organised into?

A
  • Fibril-forming collagens
  • Network-forming collagens
  • Fibril-associated collagens
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9
Q

What are the types of collagens that fall into “Fibril-forming collagens”?

A
  • TYPE I collagen fibers are found in supporting elements of high tensile strength (Skin, bone, tendon, blood vessels, cornea)
  • TYPE II collagen molecules are restricted to CARTILAGINOUS STRUCTURES (cartilage, intervertebral disk, vitreous body)
  • TYPE III collagen are prevalent in more DISTENSIBLE tissues (blood vessels, skin, muscle)
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10
Q

What are the types of collagens that fall into “Network-forming collagens”?

A

TYPE IV (basement membrane) and TYPE VIII (corneal and vascular endothelium)

both form a three dimensional mesh rather than distinct fibrils

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11
Q

What are the types of collagens that fall into “Fibril-associated collagens”?

A

TYPE IX (cartilage) and XII (tendon, ligaments and some other tissues)

both bind to the surface of collagen fibrils, linking these fibrils to one another and to other components in the ECM

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12
Q

What differentiates Collagen from other globular proteins?

A

Other globular proteins are folded into compact structures but Collagen has an ELONGATED, TRIPLE-HELIX structure that is stabilised by INTERCHAIN HYDROGEN BONDS

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13
Q

What type of protein is Collagen

A

Fibrous protein

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14
Q

Describe the structure of Collagen regarding the amino acid sequence

A
  • Rich in PROLINE and GLYCINE (smallest amino acid) which are both important in the formation of the TRIPLE-STRANDED HELIX
  • Glycine is is found in every THIRD POSITION of each polypeptide chain
  • Glycine fits into the the restricted spaces where the three chains of the helix come together
  • Glycine residues are part of a repeating sequence -Gly-X-Y- where X is frequently PROLINE and Y is often HYDROXYPROLINE (but can be HYDROXYLYSINE)
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15
Q

Describe the structure of Collagen regarding hydroxyproline and hydroxylysine

A
  • Collagen contains hydroxyproline and hydroxylysine
  • Amino acids that result from the HYDROXYLATION of some of the proline and lysine residues after their incorporation into polypeptide chains
  • hydroxylation is a POST-TRANSLATIONAL MODIFICATION
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16
Q

Describe the structure of Collagen regarding Glycosylation

A

The hydroxyl group of the HYDROXYLYSINE residues of collagen may be enzymatically GLYCOSYLATED with GLUCOSE and GALACTOSE most commonly sequentially attached to the polypeptide chain prior to TRIPLE-HELIX FORMATION

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17
Q

Describe the role of the Rough endoplasmic reticulum during biosynthesis of collagen

A
  • Synthesis of preprocollagen
  • Insertion of the pre collagen molecule into the lumen of the ER
18
Q

Describe what happens in the Lumen of ER during biosynthesis of collagen

A
  • Hydroxylation of proline and lysine residues
  • Glycosylation of selected hydroxylysine residues
19
Q

Describe what happens in the Lumen of ER and Golgi apparatus during biosynthesis of Collagen

A
  • Self-assembly of the procollagen molecule initiated by DISULFIDE BOND FORMATION in the carboxyl-terminal extensions
  • Triple helix formation
20
Q

Describe what happens in Secretory vesicles during biosynthesis of Collagen

A

Procollagen prepared for secretion from the cell

21
Q

Describe what happens extracellularly during biosynthesis of Collagen

A
  • cleavage of the propeptides
  • removal of the amino and carboxyl terminal extensions
  • self-assembly of the tropocollagen molecules into fibrils and then fibers
22
Q

Describe the synthesis of Collagen fibers

A

1) POLYPEPTIDE PRECURSORS of the collagen molecule are synthesised in FIBROBLASTS (or in related osteoblasts of bone and chrondoblasts of cartilage)
2) They are enzymatically modified and form the TRIPLE HELIX which gets secreted into the ECM
3) After additional enzymic modification, mature extracellular collagen fibrils AGGREGATE and become CROSS-LINKED to form collagen fibers

23
Q

Describe the steps in Collagen biosynthesis

A

1) Genes for pro-alpha I and pro-alpha II chains are transcribed into MRNAs
2) Newly synthesised polypeptide precursors of alpha chains (prepro-alpha chains) contain a special AMINO ACID SEQUENCE (signal sequence) at their N-terminal ends which facilitates the binding of ribosomes to the RER and directs the passage of the prepro-alpha into the lumen of the RER. mRNA is translated on the RER into prepro-alpha chains that are extruded into the lumen, where the N-terminal signal sequence is removed, converting prepro to pro (pro-alpha chain).
3) Pro-alpha chains are processed by a number of enzymes within the lumen of the RER while polypeptides are still being synthesised. Selected PROLINE and LYSINE residues are HYDROXYLATED to form HYDROXYPROLINE and HYDROXYLYSINE. Hydroxylation reactions require MOLECULAR OXYGEN, FERROUS IRON (Fe2+) and the reducing agent VITAMIN C
4) Selected HYDROXYLYSINE residues are glyccosylated with GLUCOSE or GLUCOSYL-GALACTOSE
5) Formation of procollagen begins with formation of interchain disulphide bonds between the C-TERMINAL EXTENSIONS of the pro-alpha chains. Three pro-alpha chains assemble forming a triple helix (thus Procollagen is formed). 6) Procollagen molecules move through the Golgi apparatus, where they are packaged in SECRETORY VESICLES which fuse with the cell membrane causing the release of procollagen molecules into the extracellular space
7) The N-terminal and C-terminal propeptides are cleaved by procollagen peptidases producing TROPOCOLLAGEN
8) Self-assembly of tropocollagen molecules into Collagen fibrils which form an ordered, parallel array with adjacent collagen molecules arranged in a staggered pattern. Array of collagen fibril molecules serves as a substrate for LYSYL OXIDASE (a copper-containing extracellular enzyme) which forms covalent cross-links and thus MATURE COLLAGEN FIBERS.

24
Q

Describe Type IV Collagen

A

Type IV Collagen contains a GLOBULAR CARBOXYL-TERMINAL DOMAIN which forms TROPOCOLLAGEN DIMERS. Four dimers associate at the amino-terminal domains to form a 7S domain and the tetramers form a lattice which provides STRUCTURAL SUPPORT to the basal lamina

25
Q

What is Scurvy?

A

Scurvy is a disease caused by a serious vitamin C (ascorbic acid) deficiency. Not eating enough fruits and vegetables is the main cause of the disease.

SYMPTOMS:
- Ecchymoses (bruise-like discolouration)
- Petechiae on the limbs as a result of subcutaneous extravasation (leakage) of blood due to capillary fragility
- Gum disease
- Loosening of the teeth
- Poor wound healing

TREATMENT: Increase of Vitamin C in diet

26
Q

How stable are normal collagen fibers?

A

Normal collagen fibers are highly stable molecules, having half-lives as long as several years

27
Q

What are the key components to Collagen degradation?

A
  • connective tissue is dynamic and is constantly being remodeled in response to growth or injury of tissue
  • breakdown of collagen fibers is dependent on the PROTEOLYTIC ACTION of COLLAGENASES (part of a large family of MATRIX METALLOPROTEINASES)
  • for Type I collagen, cleavage site is specific, generating three-quarter and one-quarter length fragments which are further degraded by other matrix proteinases
28
Q

What can defects in any one of the many steps in collagen fibre synthesis result in?

A

Collagenopathies

A genetic disease involving an inability of collagen to form fibers properly therefore and inability to provide tissues with the needed tensile strength normally provided by collagen

29
Q

What are the statistics regarding Collagenopathies

A

More than 1,000 mutations have been identified in 23 genes coding for 13 of the collagen types

30
Q

Describe Ehlers-Danlos syndrome

A

A connective tissue disorder that results from heritable defects in the metabolism of fibrillar collagen molecules which can be caused by a deficiency of collagen-processing enzymes and mutations in the amino acid sequences of collagen types I, III and V

SYMPTOMS:
DEFECTS IN TYPE V COLLAGEN
- skin extensibility
- fragility
- joint hypermobility
DEFECTS IN TYPE III COLLAGEN (vascular form)
- potentially lethal arterial rupture (most serious form of EDS)

31
Q

Describe Osteogenesis Imperfecta

A

Known as “brittle bone disease” and is a genetic disorder of bone fragility characterised by bones that fracture easily with minor to no trauma. Caused by dominant mutations to genes that encode the alpha I or alpha II chains in type I collagen.

Phenotypic severity ranges from mild to lethal

SYMPTOMS:
TYPE I (most common)
- mild bone fragility
- hearing loss
- blue sclera (a bluish coloration of the whites of the eyes)
TYPE II (most severe form)
- pulmonary complications in the perinatal period
- in utero fractures can be seen
TYPE III (severe form)
- multiple fractures at birth
- short stature
- spinal curvature leading to a ‘Humped back’ (Kyphotic) appearance
- blue sclerae

32
Q

Describe the most common mutation in Osteogenesis Imperfecta

A

The replacement of glycine in (Glycogen-X-Y) by amino acids with bulky side chains which prevent the formation of the required triple-helical conformation

33
Q

What are the properties of Elastin?

A
  • a fibrous protein with rubber-like properties found in connective tissue
  • elastic fibres composed of elastin and glycoprotein microfibrils are found in the lungs, the walls of large arteries and elastic ligaments
  • can be stretched to several times their normal length but recoil to their original shape when the stretching force is relaxed
34
Q

Describe the structure of Elastin

A
  • an insoluble protein polymer generated from TROPOELASTIN (a precursor which is a soluble polypeptide composed of around 700 amino acids that are primarily small and non-polar
  • rich in PROLINE and LYSINE but contains few HYDROXYPROLINE and HYDROXYLYSINE
  • Tropoelastin is secreted by the cell into the ECM where it interacts with specific glycoprotein microfibrils (such as fibrillin) which function as a scaffold onto which tropoelastin is deposited
  • some TROPOELASTIN POLYPEPTIDES are OXIDATIVELY DEAMINATED by LYSYL OXIDASE forming ALLYSINE RESIDUES. Three of the Allysyl side chains plus one unaltered side chain from the same or neighbouring polypeptides form a DESMOSINE CROSS-LINK
  • extensively interconnected, rubbery network that can stretch and bend in any direction when stressed, giving connective tissue elasticity
35
Q

Describe Marfan syndrome

A

A connective tissue disorder characterised by impaired structural integrity in the skeleton, the eye and the cardiovascular system.

Mutations in the Fibrillin-1 protein are responsible. Abnormal fibrillin protein is incorporated into microfibrils along with normal fibrillin, inhibition the formation of functional microfibrils

SYMPTOMS:
- tall
- long, slender arms, legs, fingers and toes
- 128 flexible joints
- scoliosis
- affected heart ad aorta
- increased risk for mitral valve prolapse or aortic aneurysm

36
Q

Why might patients with Marfan syndrome, Osteogenesis Imperfecta or Ehlers-Danlos syndrome have blue sclerae?

A

Due to tissue thinning that allows underlying pigment to show through

37
Q

What are the important properties of alpha1-antitrypsin (AAT)?

A
  • found in blood and other body fluids
  • inhibits a number of proteolytic enzymes (called peptidases, proteases or proteinases) that hydrolyse and destroy proteins
  • inhibits NEUTROPHIL ELASTASE (a powerful protease released into the extracellular space and degrades elastin of alveolar walls as well as other structural proteins in a variety if tissues
  • most of AAT found in plasma is synthesised and secreted by the liver (synthesis outside of liver also occurs)
38
Q

What is Neutrophil elastase?

A

a powerful protease that is released into the extracellular space and degrades elastin of alveolar walls as well as other structural proteins in a variety of tissues

39
Q

Describe alpha1-Antitrypsin (AAT) in the lungs

A
  • alpha1-Antitrypsin normally inhibits elastase released during phagocytosis by neutrophils present in alveoli of the lungs
  • in the normal lung, alveoli are chronically exposed to low levels of neutrophil elastase released from activated and degenerating neutrophils
  • proteolytic activity of elastase can destroy the elastin in alveolar walls if unopposed by the action of AAT
  • lung tissue cannot regenerate thus destruction of connective tissue of alveolar walls results in pulmonary disease
40
Q

Describe how alpha1-Antitrypsin deficiency leads to Emphysema

A

A mutation causes the normally monomeric AAT protein to misfold, polymerise and aggregate within the RER of HEPATOCYTES, resulting in decreased secretion of AAT by the liver. Due to decreased AAt secreted by the liver, blood levels of AAT are reduced as well as the amount of AAT available to lung tissues

41
Q

What are the complications of AAT deficiency?

A

The polymer that accumulates in HEPATOCYTES may result in CIRRHOSIS. The hepatic damage is a leading cause for paediatric end-stage liver failure which requires liver transplantation.

BIOCHEMISTRY (12 decks)

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