IAS07
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
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
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...)
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
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
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...)
