|
Slide 01: Sickle cell anemia - a disease of diverse populations
Caption: This computer-based lab explores the molecular biology of sickle cell anemia from DNA sequence, to protein structure, and ultimately to disorder. Students will compare sickle cell gene sequences from patients around the world to elucidate the multiple origins of the disease. Computer simulations will address questions about why the sickle cell mutation continues to persist in several areas of the world. Students will also learn about current and emerging therapies to improve the lives of individuals with this disorder.
Image: %
Slide 02: What is sickle cell anemia?
Caption: Sickle cell anemia is a genetic disease that affects hemoglobin, the oxygen transport molecule in the blood. The disease gets its name from to the shape of the red blood cells under certain conditions. Some red blood cells become sickle-shaped and these elongated cells get stuck in small blood vessels so that parts of the body don't get the oxygen they need. Sickle cell anemia is caused by a single code letter change in the DNA. This in turn alters one of the amino acids in the hemoglobin protein. Valine sits in the position where glutamic acid should be. The valine makes the hemoglobin molecules stick together, forming long fibers that distort the shape of the red blood cells, and this brings on an attack.
Image: Animation on sickle cell anemia
Slide 03: Exercise Hemoglobin - Rust or for real?
Caption: Hemoglobin consists of three basic components:
Protein component: four globin molecules form the structure (NCBI).
Organic component: A porphyrin ring is embedded into each globin molecule.
Inorganic component: Each porphyrin ring holds an iron atom.
First, the iron binds oxygen. Usually, iron forms a strong chemical bond with oxygen. Porphyrin and globin however, modulate the strength of this bond, so that the oxygen can be released in oxygen-depleted tissues to which hemoglobin is transported by the blood stream. (What do you think: could you remove rust from a car by placing it in an oxygen-free atmosphere?)
PDB's Molecule of the Month
Image: None yet
Slide 04: Dogmata
Caption: 1. DNA is transcribed into RNA, RNA is translated into proteins.
2. Sequence determins structure, which determines function.
Image: animation: DNA makes RNA makes protein
Slide 05:Exercise: Locate the globin genes in the human genome
Caption: Go to NCBI Map Viewer, search for hbb and for hba1. Then determine the location, size, and structures for the hba1 and the hbb gene. (Instructions)
Image: Nothing yet
Slide 06: Exercise: What are the differences between the hbb and the hbs genes?
Caption: Compare the sequences in Sequence Server. (Instructions)
Item: ??
Slide 07: How proteins come about I: Transcription
Caption: What you are about to see is DNA's most extraordinary secret, how a simple code is turned into flesh and blood. It begins with a bundle of factors (transcription factors)assembling at the start of a gene. A gene is simply a length of DNA instructions stretching away to the left. The assembled factors trigger the first phase of the process, reading off the information that will be needed to make the protein. Everything is ready to roll: three, two, one, GO! The blue molecule (RNA polymerase) racing along the DNA is reading the gene. It's unzipping the double helix, and copying one of the two strands. The yellow chain (messanger RNA or mRNA) snaking out of the top is a copy of the genetic message and it's made of a close chemical cousin of DNA called RNA. The building blocks to make the RNA enter through an intake hole. They are matched to the DNA - letter by letter - to copy the As, Cs, Ts and Gs of the gene. The only difference is that in the RNA copy, the letter T is replaced with a closely related building block known as \"U\". You are watching this process - called transcription - in real time. It's happening right now in almost every cell in your body.
Image: Narrated transcription animation
Slide 08: How proteins come about II: Translation
Caption: When the RNA copy is complete, it snakes out into the outer part of the cell. Then in a dazzling display of choreography, all the components of a molecular machine lock together around the RNA to form a miniature factory called a ribosome. It translates the genetic information in the RNA into a string of amino acids that will become a protein. Special transfer molecules, the green triangles, bring each amino acid to the ribosome. The amino acids are the small red tips attached to the transfer molecules. There are different transfer molecules for each of the twenty amino acids. Each transfer molecule carries a three letter code that is matched with the RNA in the machine. Now we come to the heart of the process. Inside the ribosome, the RNA is pulled through like a tape. The code for each amino acid is read off, three letters at a time, and matched to three corresponding letters on the transfer molecules. When the right transfer molecule plugs in, the amino acid it carries is added to the growing protein chain. Again, you are watching this in real time. And after a few seconds the assembled protein starts to emerge from the ribosome. Ribosomes can make any kind of protein. It just depends what genetic message you feed in on the RNA. In this case, the end product is hemoglobin. The cells in our bone marrow churn out a hundred trillion molecules of it per second! And as a result, our muscles, brain and all the vital organs in our body receive the oxygen they need.
Animation: Narrated translation animation
Slide 09: Exercise: How do proteins work?
Caption: Sequence determines structure determines function. How?
20 amino acids
Amino acid structures (3d)
Item: Nothing yet
Slide 10: Exercise: Find the amino acid sequences for hbb and hbs
Caption: Go to NCBI
Item: Nothing yet
Slide 11: Exercise: What are the differences between the HBB and HBS amino acid sequences?
Caption: HBB and HBS amino acid sequences;
EBI ClustalW;
hbb/hbs cds alignment;
Genetic code table.
Image: Not yet (bz corn)
Slide 12: Exercise: How does the amino acid difference between HBB and HBS affect the protein structure?
Caption: Align the structures of HBB with HBS at NCBI
Change Entrez to Structure, search for HBS; hit Go.
Click on 2HBS, then on the term Chain B (find the blue bar).
Check IRD_B, click on View 3D Structure.
Click Save. Maximize the Cn3D screen; align the Sequence screen underneath; close the Message Log screen.
Within the structure locate the amino acids that are different.
How do the two protein structures differ?
Item: %
Slide 13: So what is different? What causese the disease?
Caption: Examine the structures of Glu and Val here.
Item: None yet
Slide 14: Here is what's different: one amino acid
Caption: Sequence determines structure determines function.
Glu/Val
HBB/HBS
Cooperativity
Image: None yet
Slide 15: Summary of molecular analysis
Caption: This results in this, which leads to this, evoking this.
Image: none yet
Slide 16: Hemoglobin and sickle cell anemia
Caption: This animation shows hemoglobin proteins of a person with sickle cell anemia. Sickle cell anemia is caused by a single code leeter change in the DNA. This in turn alters one of the amino acids in the hemoglobin protein. Valine sits in the position where glutamic acid should be. The valine makes the hemoglobin molecules stick together, forming long fibers that distort the shape of the red blood cells causing the characteristic sickle shape of the red blood cells.
Video: hemoglobin in sickle cell anemia person
Slide 17: Human genome
Caption:
The human genome following NCBI. (Link)
Image: 3D view of hemoglobin
Slide 18: What causes sickle cell?
Caption: Mutations in the HBB gene on chromosome 11 can cause sickle cell. The beta globin protein is one of the subunits of hemoglobin, a protein necessary for the oxygen-carrying function of red blood cells. People with the sickle cell mutation in both copies of the HBB gene produce proteins that clump together and lead to changes in the shape and behavior of red blood cells.
Image: sickle cell animation
Slide 19: What is it like to have sickle cell anemia?
Caption: Interview The Pain of Sickle Cell Anemia
Video:
Slide 20: How is sickle cell anemia being treated?
Caption: Interview Treating Sickle Cell Anemia Symptoms
Image: Transposon jumping
Slide 21: Can sickle cell anemia be cured?
Caption: Mutations in the HBB gene on chromosome 11 can cause sickle cell. The beta globin protein is one of the subunits of hemoglobin, a protein necessary for the oxygen-carrying function of red blood cells. People with the sickle cell mutation in both copies of the HBB gene produce proteins that clump together and lead to changes in the shape and behavior of red blood cells.
Animation:
Slide 22: Exercise: Why does sickle cell anemia persist?
Caption: View these links and answer the question:
Geographic distribution of Sickle Cell.
Geographic distribution of malaria caused by Plasmodium falciparum..
Image: none yet
Slide 23: History of Malaria
Caption: Examine the history of malaria.
Image: Nothing yet (l1_and_alu.jpg)
Slide 24: Exercise: Simulation server - Why does the mutation persist?
Go to the DNALC Simulation Server. The survival rates for the three different genotypes are: 100% (-/-), 98% (-/+), and 3% (+/+). In malaria-infested regions these rates change to: 70% (-/-), 93% (-/+), and 3% (+/+).
Image: Nothing yet
Slide 25: Tired?
Caption: Click here
Image: Nothing yet (compare transposons and viruses.)
Slide 26: Congratulations!!!
Caption: You are so smart!
Image:
|