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The Importance of Understanding DUSP5 for Angiogenesis Prevention

The Importance of Understanding DUSP5 for Angiogenesis Prevention. Brandon S Uhler, Daniel Jashinsky, Scott Beard Marquette University, Milwaukee WI Mentor: Dr. Ramani Ramchandran Medical College of Wisconsin Advisor: Dr. Daniel Sem Marquette University. Introducing DUSP5.

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The Importance of Understanding DUSP5 for Angiogenesis Prevention

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  1. The Importance of Understanding DUSP5 for Angiogenesis Prevention Brandon S Uhler, Daniel Jashinsky, Scott BeardMarquette University, Milwaukee WI Mentor: Dr. Ramani Ramchandran Medical College of Wisconsin Advisor: Dr. Daniel Sem Marquette University

  2. Introducing DUSP5 • The DUSP5 protein plays an important role in the angiogenesis signaling cascade • It contains 2 domains • The left-hand domain was constructed via homology modeling and binds to another protein in the signaling cascade • The second domain has a phosphatase active site which is used in dephosphorylation

  3. The Purpose of DUSP5 DUSP5 • DUSP5 is essential in deactivating ERK in the Angiogenesis signaling cascade • Phosphorylated ERK is essential in continuing the signaling cascade to angiogenesis • DUSP5 removes the phosphate from pERK, terminating the cascade • If DUSP5 is not functioning properly, angiogenesis can continue uncontrollably Phosphate ERK DUSP5 ERK Continue Signaling Pathway to Angiogenesis Phosphorylated DUSP5 Signaling Cascade ends ERK

  4. Problems with Angiogenesis • If left unaltered, the angiogenesis signaling cascade will continue to produce blood vessels which can lead to growths/tumors • Studies have been done on zebrafish to analyze the relationship between DUSP5 and uncontrolled angiogenesis • If DUSP5 is unable to carry out the dephosphorylation of pERK, the signaling cascade continues beyond normal vascular development

  5. Ligand Design • In some cases, a mutation in the S147P linker causes a conformational change in DUSP5 that hinders proper pERK binding • Our goal was to design ligands that inhibit this mutation and allow for proper binding to pERK (1) (2) (3) (4)

  6. Ligand Design • The active site pocket on the DUSP5 phosphatase domain contains three positively charged arginine side chains • We attempted to place negatively charged regions in this pocket to ensure tight binding • We also looked for other potential binding sites in nearby amino acids

  7. The Next Steps • Logically, the next step in the ligand construction process is docking • One way to test the inhibitory effectiveness would be to introduce our ligands into a vascular system that contains both DUSP5 and ERK • This was done in zebrafish before, so it could be repeated with our ligand as a mutation inhibitor

  8. Learning Opportunities • Clearly, DUSP5 plays an important role in limiting harmful cell proliferation • One of the most interesting aspects of this protein is its odd shape. The two distinct domains offer an interesting look into the flexing of the protein’s tertiary structure • Monitoring exactly how this conformational change takes place would offer some insight into how the amino acid backbone shifts and contracts to allow proper binding to pERK.

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