IAS07

IAS07: Protein diversity

Fibrous proteins
  • differentiate globular and fibrous proteins
  • describe the structure of collagen and keratin

long extended repetitive sequences enable structural roles Collagen

  • most abundant protein in human body
  • ==triple helix== (3 left-handed alpha helix → right-handed superhelix)
  • Glycine-proline-hydroxyproline recur, proline side chains outside
  • self-assemble into fibrils, heads of collagen molecules form cross-striations (osteogenesis imperfecta caused by mutations in type I collagen)
  • ==vitamin C== (sodium ascorbate) required for proline hydroxylation (keep Fe2+ reduced as a cofactor for sustained prolyl 4-hydroxylase activity)   * scurvy: gum disease, loosening of teeth, malaise/lethargy

Keratin

  • 2 alpha helix → coiled coil structure → protofilament → protofibril
  • stabilized by ==disulphide bridges==, more cysteines involved in disulphide bonds → tougher keratin (some infectious fungi feed on keratin)
  • reduction/oxidation of keratin to curl hair
Oxygen-binding proteins
  • illustrate the interplay between haemoglobin and myoglobin in oxygen transport
  • explain cooperativity in ligand binding, exemplifying by haemoglobin function and carbon monoxide poisoning

Haemoglobin/myoglobin

  • haem: prosthetic group consisting of porphyrin ring, nitrogen interacts with iron ion at centre (planar) → used to carry oxygen
  • myoglobin: monomeric--single haem, single oxygen molecule, carrier of oxygen in muscle
  • haemoglobin: tetrameric (4 subunits) carry 4 haem groups, transports oxygen in blood
  • positive cooperativity: stronger binding as haemoglobin fills up with more oxygen molecules   * driven by structural change: binding of oxygen changes structure of other binding site of other subunit   * ==T state==: low oxygen affinity, binds weakly   * ==R state==: 1/2 oxygen bound, high oxygen affinity   * enables saturating of haemoglobin oxygen in lungs and release to myoglobin in tissue   * x: partial pressure of oxygen; y: proportion of sites filled   * low oxygen concentration in tissues: weak binding for release in tissues   * high oxygen concentration in lungs: strong binding for uptake of oxygen in lungs
  • carbon monoxide binds to haem competing with oxygen + disrupts haemoglobin cooperativity, locking into high affinity R-state   * 50% COHb: coma   * haemoglobin cannot release oxygen in tissues due to high affinity   * cooperativity still present in anemic individual
Protein folding & disease
  • recognize that proteins can fold into alternative conformations
  • describe how protein misfolding and aggregation associate with disease

Protein folding

  • proteins fold through progressive stabilization of intermediates, defined by amino acid sequence
  • chaperones: require ATP for folding (e.g. GroEL/HSP60)   heat shock proteins important in stress response and disease mechanisms
  • some can fold into different stable states (e.g. lymphotactin)

Diseases

prion disease: fibrous protein aggregates in brain (amyloid fibres), disease conformation can act as sites of nucleation → infectious

  • Alzheimer Disease: associated with amyloid-beta peptide → fibrils → amyloid plagues   more beta strands → aggregation
  • amyloid disease caused by protein misfolding (e.g. diabetes mellitus type 2, atherosclerosis…)

\