Protein Structure

• levels of protein structure

  1. primary
  2. secondary
  3. tertiary
  4. quaternary
• primary protein structure


  sequence of all amino acids
• secondary protein structure


  stable regional structures formed by segments of amino acids
• tertiary protein structure


  combined 3D structure of entire peptide chain
• quaternary protein structure


  conformational arrangement of two or more (polypeptide) chains
• planar peptide bond and angles of freedom

  • peptide bond has partial double-bond character
  • shorter
  • barrier to rotation: 6 atoms around peptide bond remain in a single plane
  • folding boils down to two of three dihedral angles associated with each amino acid in the chain. the third angle is fixed by partial double-bond character of the amide bond
• steric hinderance


  excluded values of phi and psi correspond to when atoms bump into each other
• importance of phi (φ) and psi (ψ)

  • not all phi and psi angles are possible (steric interference, van der waals radii)
  • ramachandran plot
• secondary structure: alpha helix

  • right handed alpha helix is -40, -60
  • easier to form turns once the first is created
  • in fibrous proteins (like myosin) long helices are often paired as coield coils
  • in globular proteins, helices and the rest of the structure are not stable on their own - all surrounding interactions are necessary for folding
• properties of alpha helix

  1. right handed (with L-amino acids) (glycine)
  2. average length: ab 12 amino acids, or ab 3 turns
  3. hydrogen bonds between every 4th peptide bond - all H-bonding groups satisfied
  4. R group side chains point outward
• secondary structure: beta strands (sheets)

  1. primary sequence zigzags in and out of the page (pleated sheet)
  2. R groups alternate facing into and out of the page (along with the zigzag)
  3. individual beta-strands align side by side to form beta-sheets (or beta-pleated sheets)
  4. hydrogen bonding occurs between adjacent strands - all groups satisfied
  5. beta-sheets can be either parallel or antiparallel
  6. orientation of individual strands
  7. h-bond geometry different
• beta turn structures

  • common in globular proteins
  • H-bonds between the 1st and 4th amino acid
  • type I
  • proline in 2nd amino acid
  • type II
  • glycine in 3rd amino acid
  • beta turns join beta strands
  • key residues: glycine (positive phi) and proline (restricted phi)
• tertiary structures

  • coiled coil
  • β-α-β loop
  • β barrel
  • silk fibroin - repeating glycine and alanine permit close beta strand packing
  • keratin
  • serum albumin
• quaternary structure

  1. more than one polypeptide chain
  2. subunits form oligomers
  3. identical subunits are protomers
  4. protomer arrangement typically symmetric
  5. cyclic symmetry
  6. dihedral symmetry
• why and how are proteins folded?

  1. minimum free-energy state = native conformation
  2. think free energy "funnel diagram"
  3. narrow for precise structure = funciton
  4. not too deep
  5. allowing unfolding for degredation
  6. allowing flexibility for function
  7. resistance to proteolysis
  8. what forces stabilized the folded state?
  9. hydrophobic interactions
  10. electrostatic (ionic) interactions
  11. hydrogen bonding
  12. van der waals interactions
  13. chemical cross-linking (disulfide, His-Zn2+, etc)
• incompletely folded proteins have potential for misfolding and aggregation

  • heat shock proteins
  • molecular chaperones that block unwanted interactions/pathways
  • hydrophobic cores are still exposed so bind to other compounds in water
• molecular chaperones

  • manage protein interactions at intermediate stages of synthesis, translocation across membranes, folding, assembly and degradation
  • expressed at high levels during stress response
  • heat shock
  • infection
  • cancer
  • drug targets
  • bind to exposed hydrophobic sites on incompletely folded client proteins
  • cycle through ATP-dependent conformational changes for binding and release of client proteins
• creutzfeldt-jakob disease (CJD) case study

  • blurred vision, lack of coordination (stumbling and falling), muscle twitching, speech impairment, sleepiness, profound confusion, disorientation, feelings of anxiety and nervousness
  • changes in personality and memory loss
  • areas of blindness
  • patient history: recent corneal transplant, use of growth hormone
  • acquired
• creutzfeldt-jakob disease (CJD)

  • rare, degenerative, invariably fatal brain disorder
  • 3 forms: sporadic (85%), hereditary and acquired (mad cow disease)
  • no diagnostic testing except autopsy. rule out other dementais (encephalitis, meningitis)
  • no cure or control. treatment to minimize symptoms, make patient comfortable
  • ab 90% of patients die within 1 year
• prion disease and transmissible spongiform encephalopathies

  • TSE - transmissible spongiform neurodegeneration, astrocytic gliosis
  • prion - proteinaceous infectious agent, once considered heretical concept for transmission (misfolded protein)
• transmissible spongiform encephalopathies (TSE)

  1. Creutzfeldt-jakob disease (CJD)
  2. causes dementia
  3. sporadic
  4. gerstmann-straussler-scheinker syndrome (GSS)
  5. causes fatal motor inhibitions/defects
  6. sporadic
  7. fatal familial insomnia (FFI)
  8. mutation
  9. inherited
  10. kuru: fore tribe in New Guinea
  11. transmitted (ate ancestors brains)
  12. wild animals and livestock (sheep scrapie, mad cow, elk chronic wasting, mink encephalopathy)

  • species barrier (however, once it enters a new species it can spread easily)
• entire structure of misfolded prion is unknown for TSE's