Lecture 3: Structure function relationships in proteins

Question 1

Heat shock proteins (Hsp) help in what processes

Answer 1

Protein folding

Question 2

Heat shock protein that helps prevent premature folding of proteins

Answer 2

HSP70

Question 3

Heat shock protein that uses ATP as a template for folding

Answer 3

HSP60

Question 4

Creutzfeld-Jacob Diseases

Answer 4

Denaturation of the prion protein in brain, causes excessive Beta sheets, which then proliferate exponentially.

Question 5

Amyloidosis

Answer 5

Aggregation/precipitation of various misfolded protein fragments produced by proteolytic cleavage. Protein precipitation/deposits cause organ failure.

Question 6

Type of amyloidosis associated with rheumatoid arthritis

Answer 6

AA amyloidosis

-Precipitation of serum amyloid A fragments

Question 7

Type of amyloidosis associated with multiple myeloma

a cancer of antibody producing plasma cells

Answer 7

AL amyloidosis

-Precipitation of antibody Light chain fragments (Bence-Jones proteins)

Question 8

type of amyloidosis associated with alzheimers’s disease

Answer 8

Aβ amyloidosis

• β-amyloid is a fragment of the amyloid precursor protein.
• Brain degeneration

Question 9

Glucose-6-P dehydrogenase deficiency

Answer 9

Proteins (hemoglobin) in red blood cells are damaged by oxygen radicals.

Proteins are denatured and precipitate in the cells (Heinz bodies).

Question 10

myoglobin vs hemoglobin structure

Answer 10

Myoglobin

• Main oxygen storage molecule in skeletal and heart muscle
• 8 α helices fold into a globular (tertiary) structure.
• The folding of helices creates a pocket in the molecule.
• The pocket binds a heme molecule (prosthetic group).
• The heme iron (Fe2+ ) binds an oxygen molecule.

Hemoglobin

• Oxygen transport molecule in red blood cells.
• Composed of 2 α and 2 β subunits (in adult hemoglobin)
• The α and β subunits are similar to myoglobin.
• The subunits are held together by noncovalent bonds.
• Has 4 heme prosthetic groups and can bind 4 oxygen molecules.

Question 11

myoglobin vs hemoglobin oxygen binding curves

Answer 11

The oxygen saturation curve of myoglobin is hyperbolic (no cooperativity).

The oxygen saturation curve of hemoglobin is sigmoid (there is cooperativity).

(In muscle (at low O2 pressure), O2 binds more strongly to myoglobin than to hemoglobin. In muscle, hemoglobin releases oxygen and myoglobin picks it up.)

Question 12

Allosteric regulator effects on O2 binding to hemoglobin
O2
H+
CO2
2,3 bisphospho-glycerate

Answer 12

O2: increases affinity

H+: decreases affinity (Protons bind better to and stabilize the deoxy form of Hb, and thus facilitate unloading of oxygen in tissues.)

CO2: decreases affinity (Dual role 1. High CO2 concentration leads to increased proton concentration.
2. Direct binding of CO2 to Hb stabilizes the deoxy form.

2,3 bisphosphoglycerate: decreases affinity (shift curve right) to release oxygen in tissues easier

Question 13

Hypoxemia at high altitudes cause

Answer 13

2,3-BPG levels increase to facilitate unloading oxygen in the tissues (curve shifts further right).

Question 14

Carbon monoxide poisoning cause

Answer 14

• CO binds ~ 220 times more tightly to heme iron than O2 and forms carboxyhemoglobin
• Reduces the O2 content of hemoglobin
• Binding of one CO to a heme group causes other heme groups to bind O2 with higher affinity (curve shifts to the left). Therefore, hemoglobin cannot provide O2 efficiently to the tissues.
• Leads to tissue hypoxia
  (oxygen does not unload easily from hemoglobin now)

Question 15

Fetal hemoglobin characteristics

Answer 15

• It has higher O2 affinity than HbA (because it has lower affinity to 2,3-BPG)
• The higher O2 affinity of HbF ensures efficient transfer of O2 from the mother to the fetus.
• Expression is beneficial in certain hemoglobinopathies (such as sickle cell disease or β-thalassemia).

Question 16

Methemoglobinemia cause and symptoms

Answer 16

-oxidation of Fe2+ to Fe3+
(cannot bind oxygen)
Symptoms: chocolate-colored blood
bluish skin and mucous membranes (cyanosis)
shortness of breath, headache, seizure.

Question 17

α-Thalassemias cause and symptoms

Answer 17

• Decreased amounts or absence of α-chain
  (Since there is not enough α chains, excess γ and β chains form homotetramers (Hb Bart’s and HbH, respectively).
  The γ and β homotetramers bind oxygen very strongly and cannot release it into the tissues.)
  Heinz bodies

Question 18

β-Thalassemias cause and symptoms

Answer 18

-Decreased amounts or absence of β-chain
(Elevated HbF and HbA2 levels (in % term).
HbF synthesis also increased.
Excess α chains precipitate in erythroid precursors, which causes inefficient RBC formation (no reticulocyte elevation).