hemoglobin · 2017-09-22 · after this lecture you will have learned: •the similiarities and...
TRANSCRIPT
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Hemoglobin: A Paradigm for Cooperativity
and Allosteric Regulation
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After this lecture you will have learned:
• The Similiarities and differences of oxygen binding to myoglobin vs hemoglobin
• How Hemoglobin is able to transport oxygen
• What allosteric regulation is, and the specific example of cooperativity.
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Cellular Requirement for O2
Catabolism
(Oxidation)
O2
ADP
ATP
NADP+
NADPH
Intermediates
Anabolism
(Biosynthesis)
Proteins
Fats
Carbohydrates
(Nutrients)
Waste
(CO2/Urea/etc.)
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Oxygen Transport
O2
O2 O2
deoxyHb
deoxyMbMbO2
Hb(O2)n Hb(O2)n
deoxyHb
deoxyHb
LUNGS MUSCLE CELL
pO2 = ~20-30 torr
RED BLOOD CELLS
O2 + 4e– + 4H+ 2H2O
pO2 = 100 torr
• Oxygen has limited solubility in Blood and Cytosol
–Use Oxygen Carriers
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Myoglobin and Hemoglobin
• Myoglobin (Mb) – Increases O2 solubility in tissues (muscle)
– Facilitates O2 diffusion
– Stores O2 in tissues (in marine mammals)
• Hemoglobin (Hb) – Transports O2 from lungs to peripheral
tissues (in erythrocytes)
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8 helices (A-H) and loops in between
The Globin Fold
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• permanent, non-proteinaceous • Incorporated during folding • • responsible for reversible O2
binding
• Fe2+ has 6 coordination sites
• 4 with N of pyrrole rings, • 2 perpendicular to ring
• 6th coordination site: none deoxyhemoglobin O2 oxyhemoglobin CO carboxyhemoglobin
The Heme Prosthetic Group
5th coordination site is occupied with proximal His
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Heme – Binding of CO vs. O2
• free heme binds C0 105 times better than O2
• kinked binding topology in Mb/Hb
favors O2 (100-fold)
TOTAL: CO binding ~ 230 fold stronger than O2
binding (Carbon monoxide poisoning)
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Ligand Binding
• Small molecules (such as metals or hormones) that bind to proteins by non-covalent interactions
• usually transient and reversible interaction • often involves “molecular breathing” of the protein, i.e.
ability to undergo small conformational changes
• often induces molecular rearrangements in the protein
• ligand binding sites are - highly conserved - complementary in size, shape, and charge
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Degree of Saturation,
0 1
[P][PL]
[PL]
]sites binding total[
sites] binding [occupied
Fraction of binding sites that are occupied by ligand at any given ligand concentration
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Degree of Saturation,
Using
[L]
[L]
[L]1
[L]
da
a
KK
K
[L][P][PL] aK]PL[
[L][P]1
a
dK
K
[P][PL]
[PL]
]sites binding total[
sites] binding [occupied
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Ligand Binding Curve
[L]
[L]
d
K
If [L] = Kd = 0.5 Kd corresponds to the ligand concentration at which 50% of the binding sites are occupied
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Some Examples for Dissociation Constants
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Figure 7-1
Myoglobin
• Small Intracellular Protein in Vertebrate Muscle
• Single polypeptide (153 aa) with one bound heme
• Facilitate O2 Diffusion in Muscle
• O2 Storage (aquatic mammals)
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Myoglobin – Oxygen Binding Curve
• binds oxygen at high pO2, releases it at really low pO2
Mb + O2 MbO2
[L]
[L]
d
K
250
2
O
O
pp
p
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pO2 in tissue ~ 4 kPa
Myoglobin – Diffusion/Oxygen Storage!
pO2 in lung ~ 13 kPa
Saturation of Mb depends on: the binding constant of Mb for O2
the concentration of O2 (pO2)
KD = p50 = 0.4 kPa
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Hemoglobin (Hb)
• present in erythrocytes • makes blood look red • 34% of weight is Hb
Different Hb subtypes:
• Hb A (adult): • two (141 aa) and two (146 aa) subunits • arranged as a pair of identical subunits
(2 subunits) • Hb F (fetal): two and two chains
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1 2
2 1
Hemoglobin – 3D Structure
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Each subunit has 1 heme, which binds 1 O2
Lehninger, Figure 7-5, 7-6
O2
Heme
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Function of Hemoglobin: Oxygen Transport
O2
O2 O2
deoxyHb
deoxyMbMbO2
Hb(O2)n Hb(O2)n
deoxyHb
deoxyHb
LUNGS MUSCLE CELL
pO2 = ~20-30 torr
RED BLOOD CELLS
O2 + 4e– + 4H+ 2H2O
pO2 = 100 torr
• O2 binding in lungs
• O2 release in tissues
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Oxygen binds to Hemoglobin and Myoglobin differently
0
0.2
0.4
0.6
0.8
1
0 20 40 60 80 100
Frac
tio
n S
atu
rate
d
pO2 (torr)
Myoglobin
Hemoglobin
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Hb’s p50 for O2 is higher than Mb.
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Hb has evolved to transport O2 pO2
In Lungs pO2
In Tissues
p50 38%
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Hb gains cooperativity by switching between 2 states
Lehninger Figure 7-10
T state (Low Affinity) R state (high affinity)
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T R
The Concerted Model All or nothing mechanism
Lehninger, Figure 7-14
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The Sequential Model
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T R
Hb follows a little of both
Lehninger, Figure 7-14
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Figure 7-8
Movements of the Heme and the F Helix During the T —> R Transition
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Local structural changes around Heme are communicated to the rest of Hb
By Janet Iwasa, https://iwasa.hms.harvard.edu/project_pages/hemoglobin/hemoglobin.html
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T vs R State
(1) Change at interface between 12 and 21
(2) R state is more compact, and relaxed
(3) T state has additional salt bridges, which makes it more tense
(4) In R state individual O2 sites have higher affinity for O2. - better Fe-O2 bond length - fewer steric repulsions associated with oxygen binding.
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Without cooperativity Hb could not efficiently transport oxygen
0
0.5
1
Frac
tio
nal
Sat
ura
tio
n (θ)
pO2
Hb
R state
T state
Lungs Tissues
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When the partial pressure of O2 in venous blood is 30 torr, the saturation of myoglobin with O2 is ______ while the saturation of
hemoglobin with O2 is ______.
A) 0.55, 0.91
B) 0.91, 0.55
C) 2.8 torr, 26 torr
D) 0.91, 0.97
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Cooperativity is measured by the Hill coefficient (HC): HC greater than 1 is for positive cooperativity, less than 1 for negative
cooperativity, and 1 for non-cooperative systems. What is the HC for Hemoglobin?
A. 3
B. 1
C. 0
D. -1
MCAT
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homotropic, positive (= cooperative binding)
Allosteric regulation of protein function
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homotropic, positive (= cooperative binding)
Allosteric regulation of protein function
heterotropic, negative
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The Bohr Effect
• H+ and CO2 are negative, heterotropic modulators of Hb
• metabolizing tissue: H+ and CO2 accumulate bind to Hb and lower the affinity of Hb for O2 Hb releases O2
• lungs: CO2 and H+ dissociate from Hb
increases the affinity of Hb for O2 Hb binds O2
• increase the efficiency of Hb as O2 transporter
Hb also binds and transports H+ and CO2 from tissue to lungs and kidneys for secretion
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Bohr effect
pH Dependence of O2 Binding to Hb
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Mechanism of Bohr Effect
Protonation of side chains
His-146+ forms salt bridge with nearby Asp-94 stabilizes low affinity T-state O2 is released as pH drops
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Figure 7-12
Roles of Hemoglobin and Myoglobin in O2 and CO2 Transport
High pH (7.6) Low [CO2]
Low pH (7.2) High [CO2]
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2,3-BPG is a negative regulator of Hb
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BPG binds to the positively charged central cavity of Hb
By Janet Iwasa, https://iwasa.hms.harvard.edu/project_pages/hemoglobin/hemoglobin.html
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BPG allows for release of O2 pO2 In Lungs At Sea Level
pO2 In Tissues
No BPG
5mM BPG
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Oxygen transport at high altitude
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At Sea Level pO2
In Tissues At 10,000 FT
pO2 In Lungs
0
0.2
0.4
0.6
0.8
1
0 20 40 60 80 100
Frac
tio
nal
Sat
ura
tio
n (
)
pO2 (torr)
Oxygen transport at high altitude
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0
0.2
0.4
0.6
0.8
1
0 20 40 60 80 100
Frac
tio
nal
Sat
ura
tio
n (
)
pO2 (torr)
At Sea Level pO2
In Tissues At 10,000 FT
pO2 In Lungs
Oxygen transport at high altitude
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0
0.2
0.4
0.6
0.8
1
0 20 40 60 80 100
Frac
tio
nal
Sat
ura
tio
n (
)
pO2 (torr)
At Sea Level pO2
In Tissues At 10,000 FT
pO2 In Lungs
5mM BPG
8mM BPG
39% 32%
Oxygen transport at high altitude
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From Protein Structure to Function
1. Hemoglobin and myoglobin: Principles of reversible ligand binding
2. (Antibodies: Principles of specific, high affinity ligand binding)
3. Myosin and actin: Protein activity modulated by ATP
4. Enzymes
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Ligand Binding can affect Protein Function
• Cooperativity – 1 ligand bound = higher affinity for more
ligands
– Concerted vs Sequential
• Allosteric regulation – 1 regulator binding affects binding of ligand
– Homotropic vs heterotropic
– Positive vs Negative
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Oxygen triggers Hb to switch from its low affinity (T) state to its high affinity (R) state. What kind of allosteric effector is
oxygen relative to Hb?
A. Heteroallosteric; positive effector
B. Homoallosteric; inhibitor
C. Heteroallosteric; negative effector
D. Homoallosteric; activator
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The major focus of oxygen transport in the blood compartment is the hemoglobin
contained in red blood cells. In contrast, the carriage of carbon dioxide by the blood
is predominantly in the form of:
A. Dissolved gas
B. Hemoglobin-bound gas
C. Albumin-attached gas
D. Bicarbonate ion
MCAT
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Table 7-1
Hemoglobin Variants
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Sickle Cell Anemia
• Glu ——> Val
– (residue 6 of -chain)
• Leads to hydrophobic interactions between hemoglobin molecules
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Sickle Cell anemia
• Hemoglobin fibers
• Sickling of erythrocytes
• Increased resistance to malaria
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Figure 7-17a
Erythrocytes
Normal Sickled
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Figure 7-20
Correspondence between Malaria and Sickle-Cell Gene