2002-2003 Projects
Human Prion Protein Dimer
Kettle Moraine High School
Students:
Ken Brockman, Aaron Eifler, Matt Gehling, Faith Hughes, Jenny Morgan, Scott Patson, Eric Powleit, Jacob Schmidt
Teachers: Karen Deboer and Pete Nielsen
Advisor: Vivien C. Yee, Lerner Research Institute, Cleveland, OH
We researched the human prion protein. Prions are associated with diseases such as Creutzfeldt-Jakob in humans, mad cow and chronic wasting disease in cattle and deer. In its normal conformation the prion protein is a folded monomer. By an unknown mechanism the protein changes shape and is able to interact with another "unfolded" prion to form a very stable complex of two prion proteins. The dimer of extended prion proteins is the pathogenic conformation. Our model tries to demonstrate this conformational change.
T Cell Receptor
New Berlin High School
Students:
Ellery Brooks, Kristin Jansen, Stephanie Rindt, Maciej Czarnecki, Kim Wirth, Scott Wirth, Alison Marlin, Ingrid Ericsson, Kevin Malec, Meghan McGinty, Angela Ludwig, Paul Carter
Teacher: Pamela Patterson
Advisor: Dr. Bonnie Dittel, Blood Research Institute, Milwaukee, WI
Our SMART team worked with Dr. Bonnie Dittel at the Blood Research Institute in Milwaukee. Her research goal is to find the cellular and molecular interactions involved in regulating immune responses. Dr. Dittel is working specifically with the autoimmune disease Multiple Sclerosis. We made a model of a T cell receptor, an important protein in regulating immune responses. An antigen presenting cell takes foreign particles in the body, breaks them up into small fragments called peptides. The peptides bind to another protein called the Major Histocompatibility Complex (MHC) and both are displayed on the cell surface. The T cell receptor recognizes the complex of MHC and the peptide fragment and initiates an immune response to help rid the body of the potentially dangerous substance.
Function: The TRCrecognizes foreign antigens displayed on MHC (major histocompatibility complex) molecules on the cell surface of antigen presenting cells.
Disease: Associated with Multiple Sclerosis; T-cells may recognize the body's own oligodendrocyte cells and initiate an immunce response that kills the oligodendrocyte. These cells are responsible for making myelin, a fatty protective covering on nerves. If these cells are killed, myelin won’t be made and MS will soon result.
Research Goal: Dr. Bonnie Dittel is looking to find the cellular and molecular interactions involved in the regulation of the immune response.
Students’ Response: We got a glimpse of research in the real world. We saw her lab and research area and all the equipment needed to do research. We realized how long it takes to make small steps in research. It takes a lot of little steps and discoveries to have a big effect on a long-term problem like MS.
Beta-amyloid Protein
Madison West High School
Students:
Elie Betlach, YuTing Deng, Beckett Jackson, Yaoli Pu
Teachers: Gary Graper and Betsy Barnard
Advisor: Dr. Brendan Orner, University of Wisconsin–Madison, Madison, WI
The Madison West SMART Team modeled the three major theoretical models of the beta-amyloid protein which forms the amyloid fibrils associated with Alzheimer's and Parkinson's diseases, as well as at least 20 other diseases. These are only proposed models since the molecular structure is not known below the fibril level. It is not known whether the toxicity of the diseases is caused by the molecule, the fibril, or the plaque formed from fibrils. There is some evidence that amyloid forms pores in membranes which causes cell dysfunction and death. We worked with Dr. Brendan Orner, a research fellow in Dr. Laura Kiessling's Chemistry/Biochemistry Lab at the University of Wisconsin–Madison. Dr. Orner's research focus is developing molecules that bind to beta-amyloid peptides and inhibit aggregation and cellular toxicity. The most fascinating thing that the team learned in addition to knowledge about Alzheimer's disease and protein structure was how to modify pdb files and create new ones with WebLab. This was necessary since we were only given small parts of the protein models in some cases, and had to arrange and aggregate those parts to show the torsion in the fibrils and keep the three models similar in scale and size for in depth comparison.
Nucleosome
St. Dominic High School
Students:
Sana Baltrusaitis, Ashley Becker, Kristin Holzhauer, Jordan Kapke, Shannon King, Alex Knauf, Allison LaGuardia, Jennifer Limbach, Sarajean Mahrt, Jackie Marcello, Kristen Pankow, Jillian Picciolo, Maureen Reardon, Melissa Ruppert, Andy Sinclair, Sarah Sladky, Katie Straub
Teacher: Donna LaFlamme
Advisor: Dr. Vaughn Jackson, Medical College of Wisconsin, Milwaukee, WI
The St. Dominic SMART Team designed a model of a nucleosome with the guidance of Dr. Vaughn Jackson at the Medical College of Wisconsin and using the pdb file 1eqz. The function of the nucleosomes is to package the long strands of DNA in the nucleus. A nucleosome is composed of an octomer of four different proteins called histones around which two loops of DNA (146 base pairs) are wrapped. Scientists are actively researching the functions of nucleosomes and are finding that they do much more than protect and compact the DNA. Enzymes interact with the N- terminal tails of the histones affecting whether genes on the DNA are silent or active. Our model of the nucleosome highlights the lysines that are involved in being methylated or acetylated. Deacetylated lysines on the histone tails are associated with silent DNA and turned-off genes. Acetylated lysines on the histone tails are associated with active DNA – turned-on genes. Our scientist mentor, Dr. Jackson, is doing research into “the specific mechanisms required to access DNA” that is wrapped around histones so that the DNA can be transcribed or replicated. One of the mechanisms he is studying, for example, is “the role of metabolic modifications such as acetylation. A common characteristic of active genes is the presence of highly acetylated histones.” Interestingly, a possible cure for a well-known dominant genetic disease called Huntington’s has been suggested in recent issues of The Scientist reporting the work of Steffan and Thompson. The potential cure is related to histone acetylation. Apparently, the mutant huntington protein folds improperly, gets cleaved, and migrates to the nucleus where it has been shown to reduce acetylation of histones H3 and H4. It does this by binding to the acetyltransferase domains of several enzymes. Mutant Huntington protein has also been shown to reduce gene transcription. Steffan and Thompson have also shown that histone deacetylase inhibitors reverse the degeneration of neurons in Drosophila models of Huntington’s disease offering hope of treatment for an incurable disease!
Adenosine Dependent Methyltransferase
St. Joan Antida High School
Students:
Vanessa Ali, Zaynab Baalbaki, Ninfa Martin, Erin Schmeling
Teacher: Mary Carlson
Advisor: Dr. James Anderson, Marquette University, Milwaukee, WI
The molecule we have created is an ado-met-dependent methyltransferase, also called Rv2118c. It is a protein that depends on adenosyl methionine to transfer methyl groups and aid in tRNA modification. This molecule is being studied for a possible connection with helping stop HIV replication. Hopefully, by mutating or altogether stopping the role of Rv2118c in tRNA modification, the virus can no longer continue replicating, therefore ending HIV replication. By using this molecule, our science advisor can be able to physically manipulate the protein and compare it to a tRNA molecule to find out how the connection and therefore mutation can be made. This was the first time any of the students from St. Joan Antida High School were involved in the Smart Team program so everything we studied was fascinating. The RasMol program and learning about rapid prototyping was interesting, and trying to understand the function of our protein was a project in itself. Everything we did, we learned through our Smart Team involvement, so the experience as a whole was fascinating and interesting.
1-Mannose-6-Phosphate Receptor
Wauwatosa West High School
Students:
Saba Ali, David Blackfield, Megan Harney
Teacher: Donnie Case
Advisor: Dr. Nancy Dahms, Medical College of Wisconsin, Milwaukee, WI
We researched the Cation-Dependant Mannose-6-Phosphate Receptor with the help of Dr. Nancy Dahms of the Medical College of Wisconsin. This protein is responsible for transporting newly-synthesized lysosomsal hydrolases to the lysosome. The lysosome is responsible for inracellular digestion. When the Mannose-6-Phosphate Receptor is defective, the lysosome does not receive hydrolases needed for digestion and the individual afflicted eventually dies because the non-working lysosome fills up with cellular matter, leading to apoptosis of the cell. This can eventually lead to the death of the organism.
The Cation-Dependent Mannose-6-Phosphate Receptor protein is a dimer, however, we decided to create only the monomer to better show the details of the structure. On the molecule you will see three disulfide bonds that are created by cysteine residues. One of these bonds is the ligand-binding site of the molecule. In addition there is also a Manganese ion, which helps in the binding of the sugar.
Von-Willebrand Factor A1 Domain Bound to the GPIb-Alpha Domain
West Allis Central High School
Students:
Jennifer Hack, Becky Habersat, Kelly Schlicht, Jeni Both
Teacher: Shari Gajria
Advisor: Dr. Phil Kroner, Blood Research Institute and Medical College of Wisconsin, Milwaukee, WI
VWF is a protein that is important in the clotting process. When a person is cut, their collagen is exposed; VWF sticks to the collagen and then becomes activated. Then platelets roll across the VWF until they find a place that satisfies them and they stick. From here, layers can be built so that a clot can form. When a person has very few, or even no, VWF present in their blood, or malfunctioning VWF, they are diagnosed with Von Willebrand Disease (VWD). Therefore, a person with VWD has blood that clots poorly, and they may bleed continuously for extended amounts of time from even small wounds. Researchers are uncertain why some people are afflicted with this disease. We are hoping that the model we have made will help give researchers a closer look into what is the determining factor that makes VWF function correctly. Dr. Phil Kroner and his colleagues would like to know why platelets sometimes stick to the VWF and sometimes do not. Hopefully seeing an up-close, detailed view of VWF, especially the A-1 domain, will help them answer this question and give them insight into why VWF sometimes malfunctions.
Student Response: We feel that the entire process has been an amazing experience that has given us many rare, valuable experiences. To be able to work with scientists at such an intimate level is something that most high school students will never have the opportunity to encounter. We hope that the work we have put into our model will help the people who are researching VWF and VED to better understand what they are looking at, and maybe even help the people who are stricken with VWD. This will be an experience that I know we will all remember for the rest of our lives, and we are very thankful for this opportunity.