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…)

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