11 Jun BIOL331 Assignment – Heterozygous and homozygous
Question
BIOL331-W17-VZ-Assignment
Learning goals
1- to apply concepts and experimental approaches learned in lectures and tutorials to find answers/solutions to
problems you have not been previously exposed to,
2- to expand your knowledge on receptor mediated endocytosis and movement of lipids in human cells,
3- to strengthen your independent learning skills by challenging you to figure out a new cellular pathway via
analysis of solid scientific evidence in combination with the use of appropriate resources.
Terms you need to review and understand before tackling this assignment:
From Genetics
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• Heterozygous and homozygous
Dominant and recessive mutations From Biochemistry and Cell Biology
• •
• • Figure 1- Low density lipoprotein What is LDL (low density lipoprotein)? See Fig 1 and
Karp (7th Ed) Chapter 8 Section 8.8 (Fig 8.44)
Karp (8th Ed) Chapter 8 Section 8.19 (Fig 8.44)
Human cells can uptake exogenous cholesterol packed in
LDL
Cells can also make endogenous cholesterol using a
pathway that involves 27 different enzymes. The most
regulated step in this pathway is the one catalyzed by an
enzyme called HMG-CoA reductase.
When cholesterol inside the cell is low, the pathway is
activated, and when cholesterol is high, the pathway is
inhibited. This regulation is called “feedback regulation”. From BIOL331 Tutorials
Radioactive labeling. Iodination involves the introduction of radioactive iodine [125I] into certain amino acids
(usually tyrosines) in proteins
From BIOL331 Lectures
•
•
• Endomembrane system
Endocytosis
Lysosomes Readings for this assignment
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•
•
•
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• The LDL receptor-JL Goldstein and MS Brown (2009) Arterioscler Thromb Vasc Biol; 29:431-438
Karp (7th Ed) Chapter 8, Section 8.9 page 319 “Experimental pathways: Receptor-mediated Endocytosis”
Karp (7th Ed) Chapter 8, Section 8.6 page 306 “The human perspective Disorders: resulting from defects in
lysosomal function”
Karp (8th Ed) Chapter 8, Section 8.18 page 297 “Experimental pathways: Receptor-mediated Endocytosis”
Karp (8th Ed) Chapter 8, Section 8.12 page 286 “The human perspective Disorders: resulting from defects
in lysosomal function”
VIDEO: ENDOCYTOSIS http://www.sumanasinc.com/webcontent/animations/content/endocytosis.html BIOL331-W17-VZ-Assignment
READING MATERIAL:
In order to answer the questions below read pages 431 to 435 of the review article “The LDL receptor” by JL
Goldstein and MS Brown (2009) , Arterioscler Thromb Vasc Biol; 29:431-438.
Do not need to read “Regulation of LDL receptors” in page 435 and page 436.
Skip to page 437 and read the final paragraph entitled “The Legacy”.
QUESTIONS
Answer the following 5 questions in D2L. Be concise and to the point limiting your answers to 70 words or less,
except for question 3 where you can use a limit of 140 words. Grades will be deducted if the answer includes
sentences unrelated to the question asked.
Q1- (5 points) Familial hypercholesterolemia
What is the main symptom of familial hypercholesterolemia (FH)?
Explain why FH was thought to be linked to a mutation in a gene product that participated in the regulation of
cholesterol metabolism as opposed to an enzyme.
Q2- (5 points) Cholesterol transport
How is cholesterol transported in the bloodstream of humans? What is “bad” and “good” cholesterol? Q3- (20 points) LDL uptake model
Brown and Goldstein obtained fibroblasts from patients homozygous for FH and were able to culture these cells in
the laboratory and compare their cholesterol uptake to normal fibroblasts. Incubation of normal cells with
labelled-LDL showed LDL is first bound to the cell and then internalized. But cells from FH patients were not able to
bind LDL and it was never internalized.
The researchers proposed the following model:
(watch the animation http://www.sumanasinc.com/webcontent/animations/content/endocytosis.html ) Figure 2- LDL uptake model- Esterified cholesterol =Cholesteryl Linoleate or Cholesteryl Oleate
Explain steps 1 to 5 of the model. Which step is deficient in FH cells? Explain what happens to the LDL receptor
after it is internalized bound to LDL. BIOL331-W17-VZ-Assignment Q4- (15 points) J.D. case
The studies shown in the figure below (Fig 3) were done using cells from an FH patient whose initials were J.D. Figure 3-Internalization and degradation at 37°C of 125I-LDL by fibroblasts from a normal subject (A) and from
J.D., a patient with the internalization-defective form of FH (B). A. ( 2points) What part of the LDL lipoprotein was labelled with 125I for these studies?
B. (3 points) What is the conclusion of this experiment?
C. (10 points) How is this explained at the molecular level and what is the role of clathrin in this process? Q5- (10 points) Enzyme replacement therapy
Explain the molecular mechanism/s involved in the delivery of enzymes (enzyme replacement therapy) for the
treatment of lysosomal storage disorders like Gaucher’s disease.
Read:
Karp (7th Ed) Chapter 8, Section 8.6 page 306 “The human perspective Disorders: resulting from defects in
lysosomal function”
Karp (8th Ed) Chapter 8, Section 8.12 page 286 “The human perspective Disorders: resulting from defects in
lysosomal function
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