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A Key to Controlling DNA St.Dominic Middle School SMART Team Instructor: Donna Laflamme, Mentor: Dr

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A Key to Controlling DNA St.Dominic Middle School SMART Team Instructor: Donna Laflamme, Mentor: Dr A Key To Controlling DNA St.Dominic Middle School SMART Team Instructor: Donna LaFlamme, Mentor: Dr. Vaughn Jackson The purpose of the St. Dominic SMART Team project was to design a physical Acetyl group binds here. model of the enzyme yHst2 Histone H4 Deacetylase using data deposited in the Protein Acetyl group cannot bind here. Data Bank and a molecular visualization program called RasMol. The designing process helped us to learn about this important enzyme’s structure, its function in the cell, and also about the chemical reaction it catalyzes. Our mentor, Dr. Vaughn Jackson, helped Carba-NAD+ Nicotinimide us understand how yHst2 controls DNA expression by removing acetyl groups from NAD+ the lysine 16 of the histone H4 tails of nucleosomes. Removing an acetyl group from + Acetyl Group lysine changes its charge from neutral to positive. This positively charged histone tail is NAD+ attracted to the negatively charged backbone of the DNA wrapped around the histones. Sir2 HistoneH4 Deacetylase Scientists have known for some time that acetylated histone tails are associated with + Carbon atom active DNA and deacetylated tails with inactive or silent DNA. Oxygen atom 2’-O-Acetyl-ADP-Ribose Our enzyme, yHst2, belongs to an important family of enzymes called sirtuins. + Zhao et. al. crystallized yHst2 with an inhibitor in the binding site to yHst2 is the yeast homologue of human Sir two 2. All Sir2 deacetylases have amino help them understand the mechanism of acetyl group transfer. All acid sequences that are very similar in all organisms from bacteria to humans. They all atoms in the normal substrate (NAD+) are the same as the atoms in the inhibitor except for one carbon.* remove acetyl groups from acetyllysine sidechains on the proteins that they target. They Acetyllysine 16 on * See arrows all use NAD+ to accomplish this. Histone H4 Sir2 proteins are very important to cells because they are involved in essential Hydrogens are Acetyl Group activites such as turning off genes, promoting the repair DNA, maintaining genome not shown Lysine 16 on Histone H4 stability, and in cell metabolism. They have even been linked to increased lifespan. For example, scientists have discovered that restricting calories can extend the life of several research organisms. They noticed that calorie restriction causes cells to have very active Sir2 enzymes. Maybe, in the future, drugs that activate Sir2 deacetylases may become a way to stay young! Doctors are already using Sir2 activators in research trials to treat the cancers, lymphoma and leukemia. Primary Citation: K. Zhao, R. Harshaw, X. Chai, and R. Marmorstein(2004) Proceedings of the National Academy of Science 101, 8563- 8568 Acetyl group Students Histone H4 fragment M ike Beining Megan Farley Becca Moore Katie Benz Drew Fink Ben Robey Last Amino Acid Brian Borges Kevin Kallinger John Selas Our model was made on the Z-Corp printer. The Z-Corp Ana Caballero John Lambert Joe Sladky Carba-NAD+ printer is like a normal ink jet printer. It has three print heads Ryan Cisler Jesse Mark Sam Sladky First Amino Acid with the colors cyan, magenta, and yellow. It also has a binder Tyler Cobb Alex Mattern Stephen Varnum print head. The only difference between the Z-Corp printer Jimmy Delforge Jim Mirda David VonRuden Carba-NAD+ is an inhibitor that is different from the natural substrate, NAD+, by one and a regular printer is that it uses plaster powder instead of Meredith Dentice Sarah Mlsna Jon Weisse atom. As you can see in the next figure the inhibitor has a carbon where NAD+ has an paper to print three dimensional models. The Z-corp printer oxygen. This small change is enough to stop the transfer of the acetyl group. does this by printing many layers. Programs like RasMol and Teacher: Donna LaFlamme AutoCAD 2000 can send images of a 3-D object, like a protein Scientist Mentor: Dr. Vaughn Jackson, Medical College of model, to the printer. The Z-Corp printer then makes the Wisconsin model one layer at a time. Supported by the National Institutes of Health (NIH) – National Center for Research Resources Science Education Partnership Award (NCRR-SEPA).
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