L20 462a_hemoglobin3_lec20_2012 - Protein function and...

Protein function and ligand binding:
Hemoglobin 3
Hemoglobin Func.on:
Fetal Hb
Mutant Hemoglobins
Lec 20 (L20) Bioc 462A
October 8, 2012

Key Concepts
• Fetal Hb (HbF) ( α
2
γ
2
) has different quaternary structure from
adult HbA ( α
2
β
2
).
– Sequence difference between β and γ reduces HbF’s affinity
for 2,3‐BPG, thus increasing its affinity for O
2
.
• HbS: surface amino acid subs.tu.on ‐‐> aggrega.on
• Examples of other mutant hemoglobins with proper.es altered
in one of the following ways:
– Muta.on in heme binding pocket leads to loss of heme.
– Muta.on disrupts ter.ary structure of a subunit.
– Muta.on stabilizes methemoglobin (Fe
3+
oxida.on state of
heme in Hb).
– Muta.on stabilizes R state, or stabilizes T state, compared
with their normal stabili.es in normal HbA.

Explain why maternal red blood cells release O
2
and fetal red blood
cells bind O
2
in the placenta, including
a) difference in quaternary structure (subunit composi.on) and
in protein primary structure between HbA and HbF;
b) effect of protein structural difference on 2,3‐BPG binding
affinity;
c) resultant difference in O
2
binding proper.es between HbA
and HbF under physiological condi.ons, i.e. at the 2,3‐BPG
concentra.on in erythrocytes in the placenta.
Describe the molecular defect in sickle cell anemia and how/why
deoxyHbS molecules aggregate.
Predict the effect of a hemoglobin muta.on on the O
2
binding
proper.es of the mutant protein, given informa.on about
nature/loca.on of the muta.on (amino acid subs.tu.on). See
examples in lecture notes and in Ch.5 problem #7 in textbook.
Learning Objec:ves

Delivery of O
2
from maternal Hb to fetal Hb
• In vivo, O
2
must diffuse across the placenta from maternal red cells (in
maternal circula.on) to fetal red cells (in fetal circula.on).