Day 10, Lecture 3: Proteins III: Fibrous Proteins Flashcards Preview

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Flashcards in Day 10, Lecture 3: Proteins III: Fibrous Proteins Deck (12):

Relevance of Fibrous Proteins 


Overview of Collagen

  • Most abundant protein (skin, cartilage, tendons, bone). About 25% of protein in adult and 15-20% of protein in child
  • Family of at least 28 different genes for use in various tissues
  • Primary structure
    • mostly GPX sequence repeats 
    • about 1000 amino acids
  • Forms triple helix of three interwined, open left-handed polypeptide helices
  • Special features:
    • Small glycine residue > helices wrap together closely
    • Peptide bonds are perpendicular to the chain axis; allows the carbonyl to point to other adjacent chains
    • Triple helices self-assemble into fibrils that reinforce tissues 
  • Post-translational modifications:
    • Proteolytic processing at several steps 
    • hydroxyproline (HP or Hyp) allows an extra H-bond to form with a peptide carbonyl from another chain to stabilize triple helix
    • Hydroxylysine (HK) 
      • site of glycosylation
    • Crosslinking of lysines
      • Adds extra strength to fibrils 


Biosynthesis of Collagen

  • mRNA→Preprocollagen, signal peptide removed during translation
  • Procollagen form has extra amino and carboxyl termini peptides
  • Proline and lysine (K) are hydroxylated by prolyl hydroxylase (note: requires cofactors Iron and vitaminC/ascorbate) 
  • HydroxyK is glycosylated
  • Prochains associate and carboxyl-termini peptides are disulfide-linked 
  • Triple helix formation is initiated at C-terminus and zips up towards N-terminus 
  • Molecule is secreted out of cell
  • Amino and carboxyl peptides cleaved to form tropocollagen
  • Self-assembly of many tropocollagens into a 1/4 staggered array
  • Cross-linking of lysines initiated by action of lysyl oxidase (note: copper is cofactor) - makes allylysine=all. Then Schiff base formation with another K. 


Collagen roles in aging, cell adhesion, wound healing 

  • Aging
    • More cross-linking of the lysines of collagen molecules with time, therefore fibers stiffen as one ages 
  • Cell adhesion
    • In addition to structural roles, collagen fibrils interact with other cell surface and matrix molecules (e.g. Integrins, fibronectin, laminin and proteoglycans) which in turn bind to other cell surfaces 
  • wound healing
    • Scar tissue
      • consists mostly of collagen (Ex. Liver Cirrhosis; after damage from virus,alcohol or drugs, dead cells are replaced with collagen fibers 
    • Tissue remodeling and repair requires controlled collagen degradation
    • In infection, the abscess is normally walled off with collagen to contain the microbes, but some bacteria secrete collagenases to digrest the protective barrier and escape into the surrounding tissue 



  • Disease of Defective Collagen
  • Vitamin C (ascorbate) is required for Hydroxyproline formation
  • Deficiency leads to a triple helix that is not stabilized by extra H-bond from this special AA
  • Therefore triple helix "melts" at body temperature 


Osteogenesis Imperfeta 

  • "brittle bone disease"
  • Disease of defective Collagens
  • Typically a point mutaiton (usually glycine to X) impairs triple helix formation
  • Particulary bad for the structure when mutation at the C-terminus (collagen zips up C→N direction) and the folding process stalls out early 


Ehlers-Danlos Syndrome

  • "rubber or elastic man" 
  • Disease of Defective Collagens
  • Heterogeneous group with: stretchy skin, loose joints, poor wound healing, failure of vessel/organ structures 
  • Typically caused by no cross-linking (no strengthening) or Failure to remove N-peptides (collagen not converted to most insoluble form) 
  • remember crosslinking requires Lysyl oxidase and copper 


Effect of Mutations in a Multimeric Protein

  • Collagen is a triple helix that can be made of more than 1 species of polypeptide (depending on the fiber and the tissue)
  • There are 2 alleles of each collagen gene species (remember about 28 families) per diploid cell
  • Two Scenarios:
    • Bad gene is a null or nonsense mutaiton (and the defective polypeptide is degraded quickly):
      • 50% of the normal collagen fibers are made 
        • patient outcome: mild to moderate disease
    • Bad gene is a missense mutation in which the defective polypeptide does not fold correctly but still incorporates into collagen fibers:
      • 3/4 of all of the fibers are bad since poisoned with the faulty subunit
        • Patient outcome:
          • Severe to lethal disease. Dominant 



  • The "rubber" protein forms a 3-dimensional network of cross-linked polypeptides 
    • Primary structure:
      • mostly small nonpolar AAs, plus alot of Pro (causes kinks) and Lys (K) (sites for cross-linking)
    • Lysine crosslinks
      • 2 chains together with 4 cross-links called desmosine (initiated by lysyl oxidase) 
    • Reversible stretching
      • Elastin helps large arteries act as a secondary pump in circulatory system because heart is a pulsatile pump > stores energy and smooths out blood flow 


Alpha-1 antitrypsin deficiency

  • Alpha-1 antityspin (alphaAT) : 
    • protease inhibitor produced in the liver
  • Disease causing gene alterations result in abnormal folding of the protein
    • Decreased activity
    • failure to be normally secreted from the cell
    • accumulaiton within the cell 



  • Primary structure
    • Tandem repeats of 7 AAs (the equivalent of two turns of an alpha-helix) that form a nonpolar and a polar surface
    • Form micro to macroscale→ alpha helix, protofibril, microfibril, macrofibril of hair
    • Many cysteines that are cross-linked so that keratin fibrils are insoluble and resistant to stretching (permanent waves undo Cys cross-links)  


Effect of smoking on elastin in the lungs

  • Emphysema
    • inflammatin leads to loss of elastin 

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