Abstract

Wnt signaling is essential to regulate embryonic development and adult tissue homeostasis. Aberrant Wnt signaling is associated with cancers. The ER-resident membrane-bound O-acyltransferase Porcupine (PORCN) transfers a palmitoleoyl moiety to Wnt. This lipidation is indispensable for Wnt binding to its receptor Frizzled, thereby initiating signaling. Once modified, Wnt is transported to the cell surface via binding its transporter Wntless. In the lecture, the speaker will report four cryo-EM structures of human PORCN in the distinct states. Moreover, the speaker and his group’s recent cryo-EM and mass spectrometry studies have identified a Wnt chaperone that is essential for Wnt transfer from PORCN to Wntless and its secretion. Their structural and functional analyses with molecular-dynamics simulations demonstrate that a phospholipid in the core of Wnt-bound Wntless regulates the association and dissociation between Wnt and Wntless, suggesting a lipid-mediated Wnt secretion mechanism. Together, their works provide a mechanism of Wnt production and advance the development of PORCN inhibitors for cancer treatment.

About the Speaker

Prof. LI Xiaochun received his BS in Chemistry and Biology in 2008 and finished his PhD training in Structural Biology in 2012, both at Tsinghua University. His postdoctoral studies as a Life Science Research Foundation Fellow were conducted at the Rockefeller University. In 2017, he joined the faculty at the University of Texas (UT) Southwestern Medical Center. He is currently an Associate Professor and a Rita C. and William P. Clements, Jr. Scholar in Biomedical Research in the Department of Molecular Genetics and the Department of Biophysics at UT Southwestern Medical Center.

Prof. Li’s research focuses on membrane proteins in cholesterol biogenesis, transport, and signaling using multiple approaches from protein engineering to x-ray crystallography and cryo-EM. He is the recipient of 2019 Damon Runyon-Rachleff Innovation Award, 2023 American Heart Association Established Investigator Award, and 2023 G. Harold and Leila Y. Mathers Foundation Award.

For Attendees' Attention

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