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Center for BioMolecular Modeling …where teachers come first. SHP-2 Has Awakened—Let’s Divide! West Bend East High School SMART Team 2006: Jared Blommel, Jen Donegan, Tyler Hinchey 1305 E Decorah Rd. 53095. Instructor: Trish Strohfeldt Mentor: Debra K. Newman, Ph.D. Associate Investigator Blood Center of Wisconsin Milwaukee, WI 53201-2178 Let’s Divide! The figure below shows the process of how SHP-2 is activated and binds with a phosphate group to induce cell division. What Regulates Cell Division? Abstract Noonan’s Syndrome The SYP tyrosine phosphatase, also known as SHP-2, is an enzyme that cleans phosphates off of the amino acid tyrosine. SHP-2 has three sections, including an aminoterminal SH2 domain (N-SH2), a carboxyl-terminal SH2 domain (C-SH2), and a phosphatase domain (PTP). The NSH2 domain of SHP-2 is a specific section that regulates the activity of the PTP domain. When inactive, the N-SH2 domain of SHP-2 binds with the PTP domain of the same molecule and keeps it "off." When active, the N-SH2 domain of SHP-2 binds with phosphate -containing tyrosine amino acids on SHP-2 binding proteins (BP), which releases the PTP domain of SHP-2 and enables it to turn "on.“ The SHP-2 molecule is an indispensable regulator of cell division and reproduction. In animals that are SHP-2 deficient (for example, experimental mice in which the SHP-2 gene has been "knocked out"), cell division is so abnormal that even the embryo does not develop. Mutations (shown above in purple ) in the NSH2 domain of SHP-2, prevent SHP-2 from binding to itself, resting, and allowing regulation of cell division. This can cause Noonan’s Syndrome. Noonan’s Syndrome affects 1 in 1,000 to 1 in 2,500 males and females equally worldwide. A B Binding to SHP-2 Clockwise from left: A.) Webbed neck B.) Deformity of sternum and widely spaced nipples C.) Downward eyeslant, bulging eyes, and low set ears SH2 domain With phosphotyrosine receptor 90 degree turn The model includes a small piece (which we refer to as a “peptide”) of another protein, the PDGF- R (Platelet-Derived Growth Factor-Receptor; shown in magenta), which binds to the amino-terminal SH2 domain of SHP-2 (amino acid residues involved in binding shown in green) and activates the enzyme. By activating the enzyme, cell division occurs and then regulates the body’s functions. PDGF-R PECAM PECAM (Platelet Endothelial Cell Adhesion Molecule) and PDGF- R are two molecules that bind to SHP-2 with the shared amino acids highlighted in red. They also share a common phosphate group (highlighted in orange) that must be added to a tyrosine residue in either peptide so that it can bind to the SHP-2 molecule. Both peptides help regulate cell division. C www.infobiogen .fr Other symptoms include short stature, learning problems and deafness Conclusion SHP-2 was an interesting molecule to study because it has such a profound effect on the body. As a team we enjoyed researching this enzyme, the peptides that bind to it, and the effects of Noonan’s Syndrome. We hope that more studies will be done on the binding process and Noonan’s Syndrome so it can be prevented. Supported by the National Institutes of Health (NIH) – National Center for Research Resources Science Education Partnership Award (NCRR-SEPA)
