4. Fibrous Proteins- Collagen and Elastin Flashcards
Features of Fibrous Proteins
Have high α-helix or β-sheet content A repeating motif usually present Long, rod-like structure Often mechanically strong & highly cross-linked Usually insoluble Usually play a structural role -Extracellular Matrix (ECM) Examples: *Collagen *Elastin Keratin
Extracellular Matrix (ECM)
*The “grout” that holds cells together
ECM contains 3 classes of molecules:
-1. structural proteins (collagens and elastins)
-2. protein-polysaccharide complexes to embed the structural proteins (proteoglycans)
-3. adhesive glycoproteins to attach cells to matrix (fibronectins and laminins)
Types of Collagen
(*29 types known so far; types I-IV = 90% of all tissue collagen)
- Fibril forming
- I. skin, bone, tendon, blood vessels, cornea
- II. Cartilage, intervertebral disc, vitreous body
- III. Blood vessels, fetal skin - Network-forming
- IV. Basement membrane
- VII. Beneath stratified squamous epithelia - Fibril-associated
- IX. Cartilage
- XII. Tendon, ligaments, some other tissues
Functions of Collagen
Collagens are the most abundant proteins in the body
They occur in connective tissues where tensile strength is needed
e.g., skin, tendons, cartilage, bones
Tensile strength results from the use of:
- The triple helix secondary structure
- The assembly of tropocollagen subunits into a fibril
- Chemical cross linking of fibrils to strengthen the collagen fiber
Structure of Collagen
- collagen=triple helix, but NOT α helix
- principal component of connective tissue (tendons, cartilage, bones, teeth)
- basic unit=tropocollagen:
- 3 intertwined polypeptide chains (1000 residues ea)
- MW=285,000 (for 3 strands altogether)
- 300 nm long, 1.4 nm diameter
- unique AA composition
Collagen is formed from tropocollagen subunits. The triple helix in tropocollagen is highly extended and strong.
Features of Collagen Triple Helix
-Three separate polypeptide chains arranged as a left-handed helix (note that an α-helix is right-handed)
-3.3 residues per turn
-Each chain forms hydrogen bonds with the other two: STRENGTH!
»Remember that in α-helix, the H-bonds occur between amino acids in the same chain
Amino Acid Composition of Collagen
*Nearly one residue out of three is Gly (most abundant amino acid in collagen)
Repeating motif is Gly-X-Y
-X is often Pro
-Y is often hydroxylysine or hydroxyproline
Proline content is unusually high
Modified Amino Acids in Collagen
Amino acid modifications stabilize collagen triple helix:
4-hydroxyproline
3-hydroxyproline
5-hydroxylysine
- Ascorbate (Vitamin C) is an essential cofactor for the Pro and Lys hydroxylation reactions (result in structures w hydroxyprolyl residue w OH attached)
- Scurvy symptoms such as sore, spongy gums, bruising and poor wound healing occur in Vitamin C deficiency due to defects in collagen structure
Collagen Biosynthesis
must know key steps in the biosynthesis of mature collagen fibers
- Genes for pro-α-collagen transcribed into mRNA
- mRNA translated in cytosol and transcribed into pro-α-collagen polypeptide in ribosome on RER (signal sequence removed)
- Some Pro and Lys hydroxylated (+OH gp)
- Some Hydroxy-Lys glycosylated with glucose and galactose
5) 3 pro-α-chains assembled into triple helix - N- and C-termini stabilized by disulfide bonds to produce procollagen (triple helix formed by zipper-like folding)
- Procollagen is secreted from Golgi vacuole into ECM
- Propeptides at N- and C-termini cleaved (EXTRACELLULARLY) by procollagen peptidases to generate tropocollagen
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Roles of enzymes
-intracellular prolyl hydroxylases- triple helix assembly and collagen deposition
-intracellular lysyl hydroxylases- collagen fibril assembly
-extracellular lysyl oxidases- collagen fiber crosslinking
Crosslinks in Collagen Fibrils
*Crosslinks between Lys and oxidized Lys (Allysine) facilitate collagen fibril formation
*Lysyl oxidase, located in the extracellular matrix (ECM) is a Cu-containing enzyme
In Menkes disease, a genetic defect in ATP7A gene causes poor distribution of copper in the body
Lack of copper in some tissues results in defects in bone, skin, hair, blood vessels and the nervous system
Coarse kinky hair, loose skin and joints are some of the symptoms of Menkes disease
Collagen – From Polypeptide to Fiber
In ER lumen-
1) 3 precursor α chains assemble into procollagen (triple helix w loose ends)
After secretion from cell-
2) Procollagen peptidase turns procollagen into collagen molecule (tropocollagen)
- Assembly of tropocollagen results in collagen fibril (crosslinking) (67 nm width?)
- Assembly of collagen fibrils results in collagen fiber
Osteogenesis Imperfecta (collagenopathy)
Also known as Brittle bones syndrome
Type I – OI tarda: long bone fractures prior to puberty, hearing loss, *blue sclerae
-Decreased production of α-chains
Type II – OI congenita: more severe, frequently lethal, multiple fractures at birth, kyphosis, *blue sclerae, respiratory problems
-Substitution of Gly with amino acids bearing bulky side chains
Ehlers-Danlos Syndrome (collagenopathy)
Connective tissue disorders commonly due to defective processing of Type III or V
*Decreased expression of lysyl hydroxylase or N-procollagen peptidase
May also result from mutations in collagens Type I, III or V
Skin extensibility (stretchy skin) – Type V
Joint hypermobility (contortionists) – Type V
*Arterial rupture – Type III
Elastin
While collagen has high tensile strength, elastin is a connective tissue protein with rubber-like properties
Gives tissues and organs the capacity to stretch without tearing
*Found in lungs and walls of large blood vessels, elastic ligaments, and skin
Synthesized as a soluble monomer called “tropoelastin”
Composed primarily of small, non-polar amino acids (e.g., glycine, alanine, valine)
Also rich in proline and lysine
Elastin fibers are crosslinked using *desmosine links (and isodesmosine links in pic)
Elastin Structure
Elastin is mainly composed of Glycine (33%), Alanine (23%), Valine (13%) and Proline + HydroxyProline (10%)
Side chains of these hydrophobic amino acids do not form hydrogen bonds
-Allows the core of elastin to separate and stretch
Elastin forms its own special helical structure made up of repeated β-turns
-β-spiral
