collagen elastin and a1-antitrypsin Flashcards
What is collagen ?
Most abundant protein in human body.
A fibrous protein with long and rigid structure,
Forms structural component in different tissues and organs
There are mutiple genes meant for collagen synthesis, which are located in different chromosomes
In general collagen is made up of three α polypeptide (protein) chains
Each α chain contains about 1000 a.a. residues
The 3 chains are wound around each other to form a rope like structure - Triple helix.
In triple helix the α chains are held together by hydrogen bonds.
Type I collagen contains two α1 chains & one α2 chain
Type II collagen – three α1 chains
Variations in a.a. sequence of α chains result in different types of collagen with different properties
More than 25 types of collagen occur in human bodies - Type I, II, III, IV, V —– etc
They are distributed in different parts of body such as bones, skin, cartilage, tendons, blood vessels, cornea, basement membrane etc
Based on the location functions collagens are categorized into different groups:
Fibril forming
network forming
fibril associated
fibril forming: type 1 , type 2 type 3 and type 4
type 1: bone ,tendons, cornea, skin
type 2: cartilage
type 3: kin and blood vessels
network forming: type 4 forms the basement membrane and type 8 forms the vascular endothelium
fibril associated: type 9 and type 12 associated with linking collagen fibrils to one another components of the extracellular matrix
How can collagen be arranged ?
dispersed as gell in extracellular matrix and vitreous of the eye
bundled into parallel fibers in tendon to provide strength
stacked in cornea to transmit light with minimal scattering
arranged in fibers of bone
what is the structure of collagen
What is each chain rich in?
what is the general strict of each chain?
what is the x position frequently occupied by?
What are hydroxyproline and hydroxylysine?
What is the triple helix stabilized by?
- The 3 α - polypeptide chains form triple helix
- Each chain is rich in amino acids glycine and proline
- Glycine being smaller, fits into the restricted space
- The general sequence of each chain is;
- —- Gly-X-Y-Gly-X-Y-Gly-X-Y ——-
- Glycine represents every third amino acid in the sequence
- X position is frequently occupied by proline & Y occupied by hydroxyproline (or sometimes hydroxylysine)
- Thus frequently the sequence of the α - chain may be (Glycine - proline - hydroxyproline)
- Hydroxyproline & hydroxylysine are modified amino acids formed by hydroxylation of proline & lysine respectively
- Triple helical structure is stabilized by interchain hydrogen bonds
What are the roles of proline, hydroxyproline and the hydroxyl group of hydroxylysine ?
What are hydroxylation of proline and lysine dependent on?
Proline (by virtue of its ring structure) facilitates helical structure of the α - chain by causing the kinks
Hydroxyproline is needed to stabilize triple helical structure by forming hydrogen bonding. It is a modified amino acid
Hydroxyl group of hydroxylysine is involved in enzymatic glycosylation of collagen
Hydroxylation of proline & lysine is vitamin C (Ascorbic acid) dependent reaction
Where is collagen synthesized?
synthesized in the fibroblast ( also in the osteoblast and chondroblasts)
- synthesis in the RER as as prepro-a-chain with as signal sequencce at its N-terminal. In the lumen of the RER the signal sequence is cleaved off and pre-pro collagen is converted into pro-a-chain
- hydroxylation of lysine and proline on the Y position by proply hydroxylase and lysly hydroxylase ( requires vit c AKA ascorbic acid, Fe and O2)
- some hydroxylysine undergo glycosylation with glucose and galactose
- three pro-a-chain assemble exhibiting: disulphide binds at the non helical c-terminal and n-terminal regions and triple helix at the centre
- once the triple helix is form is complete the resulting structure becomes pro collagen
- the triple helix procolagen moves form the ER to the golgi by exocytosis
- in the extracellular space the non-helical N and C terminal regions (having disulfide binds) of pro collagen are cleaved by pro -collagen peptidases forming tropocollagen
- individual tropocollagen molecule assemble together to form collagen fibrils
- mature collagen fibres are formed by cross-linking of individual fibrils
- the cross-linking is facilities by lysine and hydroxylysine of collagen
- First, some of the lysine & hydroxylysine residues are deaminated by copper containing enzyme lysyl oxidase to form allysine and hydroxyallysine.
Next, allysine & hydroxyallysine present in one collagen molecule condense with lysine & hydroxylysine of another collagen to form covalent cross-links to form mature collagen fibers
How is collagen degraded?
Collagens have relatively long half lives
Breakdown of collagen fibers is initiated by collagenases (a family of metalloproteinases) present in matrix
Osteogenesis imperfecta (OI)
Also called as brittle bone syndrome
Several cases of OI also exhibit blue sclera
Abnormality of teeth development may also be OI
Caused due to Mutation of genes coding for the synthesis of either α-1 or α-2 chain of collagen I
Gene mutation may lead to:
i) Decreased production of collagen I
or
ii) Defective formation of collagen I
Defective formation of collagen I is mostly caused by the gene mutation where glycine is replaced by another amino acid with bulky side chain
Type I OI: Most common, mild bone fragility, hearing loss & blue sclera
Type II OI: Lethal in perinatal period due to pulmonary complications. In utero fractures seen in the fetus
Type III OI: Severe. Multiple fractures at birth, short stature, spinal curvature – leading to humped back (kyphotic) appearance, blue sclera
Children with OI may be treated with bisphosphonates
The drug inhibits osteoclastic activity of bones, thereby aids to maintain bone mass & tensile strength
The incidence of fracture in OI may be confirmed by Prenatal diagnosis (ultrasound examination in pregnant uterus)
Ehlers-Danlos syndrome (EDS)
A heterogenous group of disorders
Could be due to the deficiency of collagen processing enzymes such as lysyl hydroxylase or procollagen peptidase
Could also be due to mutation in amino acid sequences in collagen type I, III or V
Classic form of EDS: Defect in type V collagen, Fragile stretchy skin and loose joints with poor strength of connective tissue
Vascular form of EDS: More severe, Defect in type III collagen - causes arterial rupture
Both of these forms of EDS are autosomal dominant disorders
Elastin
A prominent connective tissue protein
Insoluble protein, elastic in nature
Mainly present in lungs, wall of arteries, skin and elastic ligaments
In connective tissues elastin interacts with another protein, fibrillin
Elastin is synthesized in RER as tropoelastin, a linear polypeptide
Only one pair of genes codes for the synthesis of elastin (unlike collagen)
Rich in small & non polar amino acids - glycine, alanine & valine
Proline & lysine are also present significantly
Very few hydroxyproline and hydroxylysine
Some of the lysine residues undergo oxidative deamination by the action of lysyl oxidase (Copper containing enzyme) to form allysine residues
Three allysyl side chains and one unaltered lysyl side chains present in same or neighboring polypeptides form a desmosine cross link – facilitates stretchable capacity of the elastin
What is the effect of a1-antitrypsin? Where is it synthesized?
Elastin is an important protein in alveolar walls of lungs
Elastin is under threat of proteolytic effect by neutrophil elastase
However, in normal condition this threat is overcome by the action of α1-antitrypsin
α1-antitrypsin is a plasma protein (belongs to α1-globulin group), capable of inhibiting proteolytic enzymes such as trypsin & elastase
α1-antitrypsin is mainly synthesized in liver
It protects lung elastin by inhibiting the activity of neutrophil elastase in lung alveoli, & thereby maintains normal alveoli function
Deficiency of α1-antitrypsin leads to damage of lung elastin caused by elastase
This causes pulmonary emphysema, a type of chronic obstructive pulmonary disease (COPD) due
What is a1-antitrypsin deficiency due to? Ppt which a1-defiency are advised to do what and why?
α1-antitrypsin deficiency could be due to:
Genetic deficiency of α1-antitrypsin (Autosomal recessive disorder)- point mutation
– Replacement of glutamate by lysine at position 342 of α1-antitrypsin is a prominent abnormality in most of the cases
– The defective α1-antitrypsin may undergo polymerization in liver cells – may result in liver cirrhosis
- Genetic deficiency of α1-antitrypsin Common among North European Caucasians
– Could be treated by α1-antitrypsin therapy (either by intravenous administration or aerosol inhalation)
The patients with α1-antitrypsin deficiency are advised to avoid cigarette smoking – because chronic smoking results in oxidative damage to one of the crucial methionine residues (required for binding with elastase) of α1-antitrypsin– thereby affecting its activity – worsening the complication of emphysema
