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2018 Scientific Report

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Center for Cancer and

Center for Cancer and Cell Biology WEI LÜ, Ph.D. Wei Lü earned his Ph.D. from the University of Freiburg in the laboratory of Oliver Einsle. He then was a postoctoral fellow in the laboratory of Eric Gouaux (HHMI/Vollum Institute) before joining VARI as an Assistant Professor in 2017. RESEARCH INTERESTS We use single-particle cryo-electron microscopy and other biophysical/biochemical methods to study the structure and mechanism of ion channels and transmembrane receptors that are linked to neurological diseases and cancers. We recently determined the cryo-EM structure of the human TRPM4 channel. STAFF Yihe Huang, Ph.D. Michelle Martin, A.A. Paige Winkler, Ph.D. STUDENT Wooyoung Choi 10 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT

KARSTEN MELCHER, Ph.D. Dr. Melcher earned his master's degree in biology and his Ph.D. in biochemistry from the Eberhard Karls Universität in Tübingen, Germany. He was recruited to VARI in 2007, and in 2013 he was promoted to Associate Professor. RESEARCH INTERESTS Our laboratory studies the structure and function of proteins that have central roles in cellular signaling. To do so, we employ X-ray crystallography and cryoelectron microscopy in combination with biochemical and cellular methods to identify mechanisms of signaling and frameworks for the rational design of new and improved drugs against diseases such as cancer, diabetes, and neurological disorders. STAFF Xin Gu, M.S. Michelle Martin, A.A. STUDENTS Zachary DeBruine, B.S. Yan Yan, B.S. VISITING SCIENTIST Feng Zhang, Ph.D. AMP-activated protein kinase (AMPK) AMPK is a central regulator of energy homeostasis and important drug target for the treatment of metabolic diseases, including diabetes, obesity, and cancer. AMPK senses the energy state of the cell by competitive binding of AMP, ADP, and ATP to three sites in its γ subunit. We are determining the structural mechanisms of AMPK regulation by direct binding of AMP, ADP, ATP, and various drugs, as well as by post-translational modifications. Plant hormone signaling We are studying perception, signal transduction, and target gene regulation for hormones that reprogram plants in response to drought and other abiotic stresses (abscisic acid), to herbivorous insects and microbial pathogens (jasmonates), and to mineral nutrient stresses (strigolactones). These stresses are responsible for major crop losses worldwide and have a large impact on human malnutrition. WNT reception and signaling WNTs are morphogens that have key roles in human development and stem cell maintenance; components of the WNT signaling pathway are frequently mutated in cancers, as well as in bone and retinal diseases. This pathway is therefore an important therapeutic target. Yet, how to therapeutically target the docking of a WNT to its cell surface receptor complex, and the molecular mechanism of how such docking transduces signals to the inside of the cell, have remained elusive. We are using a combination of structural and live-cell analysis to determine the structure of the intact receptor complex and the mechanism of WNT transmembrane signaling. VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 11

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