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...)