Specialization of Proteins III Flashcards
1
Q
Describe the T(ense) configuration of hemoglobin
A
- Hb has lower oxygen affinity
- salt bridges among residues that confer stability of protein
- iron pulled away from plane of heme (difficult for O2 binding)
- proximal histidine is bound to iron
- as long as O2 not bound, histidine is not pulled and will not rotate teh protein to expose another binding site for oxygen
2
Q
Describe the R(elaxed) configuration of hemoglobin
A
- higher oxygen affinity
- salt bridges between residues lost due to rotation
- binding of oxygen pulls iron into plane of heme and helps stabilize R state
- pulling of iron into plane of heme also pulls proximal histidine, which is bound to iron; this twists the configuration of the protein, exposing another active site for oxygen to bind = cooperative binding
3
Q
How does cooperative binding of oxygen by Hb improve its effectiveness as an oxygen transporter?
A
- when oxygen binds to iron, it induces a change to the R form in those other subunits by pulling iron into the plane of heme and also pulling the proximal histidine (conformational change of protein). This ruptures salt links in other parts of the protein, freeing up another subunit to bind to oxygen
- this characteristic gives Hb a sigmoid affinity curve for oxygen. in the lungs where PO2 is high, Hb is saturated. In tissues where PO2 is lower, Hb affinity for oxygen is lower and oxygen can be released from Hb to be delivered to tissues
4
Q
What is the Bohr Effect (protons)?
A
- occurs due to metabolism at the body tissues
- protons are a product of metabolism and raise the pH of the tissues
- histidine is basic at phsyciologic pH and will become protonated (gains a proton and positive charge)
- now the histidine+ will interact with other residues, forming a salt bridge and pushing the protein into the T configuration
- oxygen affinity is lower in this configuration and so oxygen is more likely to be delivered to the tissues
- during active metabolism, this effect helps to ensure that oxygen dissociates from Hb
5
Q
What is the effect of carbon dioxide on Hb affinity for oxygen?
A
- CO2 is also product of metabolism (aerobic)
- enters cell and binds Hb at its N-terminus, forming a carbamino group that induces a salt link between N-terminus and one of alpha helices
- salt link stabilizes T form, lowering affinity for oxygen
- this also ensures oxygen delivery during active metabolism
- some carbon dioxide is converted to acid; this allows protonation of histidine in same fashion as Bohr effect
6
Q
What is effect of BPG on Hb affinity for oxygen?
A
- product of RBC when PO2 is low
- fits int the cleft that opens when Hb rotates from R to T state
- stabilizes T state (one per Hb molecule) and decreases oxygen affinity
- allows oxygen to bind cooperatively to Hb
- at high altitude, there is increase in BPG
7
Q
What is effect of the gamma subunit on Hb affinity for oxygen?
A
- gamma subunit has fewer positively charged residues that interact with BPG (4 instead of 6 in HbA1), so binding of BPG is less in fetal Hb. This means that the Hb is more likely to be in R form
- fetal Hb has a higher affinity for oxygen, ensuring oxygen will move from mother’s Hb to the fetus
8
Q
How does carbon monoxide (CO) compete with oxygen for binding to Hb?
How is CO’s greater affinity relative to O2 is reduced by distal histidine?
A
- CO also binds to the ferrous iron in Hb, with a 200x greater affinity than oxygen
- it is sterically hindered by the distal histidine from binding straight on (if it were able to, affinity would be 10000x higher)
- CO is highly toxic
9
Q
What is the relationship between Hb and acid-base homeostasis?
A
- the body has a buffer system (with weak acids) to prevent changes in pH
- Hb absorbs 50% of aerobically produced protons on the histidine residues
- 15% of metabolic CO2 binds to the N-termini of globin chains, so it can’t react with water to form H+
- Hb helps prevent metabolic acidosis
