Yuh Min Chook, professor and Alfred and Mable Gilman Chair in Molecular Pharmacology at The University of Texas Southwestern Medical Center, is interested in understanding how proteins move between the cytoplasm and the nucleus. She is studying a family of nuclear transporter proteins – ten that ferry proteins into the nucleus, thus named importins, and ten exportins that bring proteins out – to understand the process, of which much is still unknown.
“Why does the cell need so many different types of nuclear transporters? How do they determine which type of cargo protein goes with which type of transporter? What are these proteins they are carrying? What functions do they fulfill for the cell? So many questions!”, Dr. Chook said.
By studying the physical and cellular mechanisms of nuclear-cytoplasmic transport, her research seeks to understand molecular recognition in this system and to discover new classes of nuclear localization and export signals.
“This is a very fundamental process,” she explained. “Every cell more advanced than bacteria – with the exception of red blood cells, which lack a nucleus – uses nuclear transporters, or importins and exportins. We are still a long way from understanding the many routes the cargoes take and the proteins that hitch a ride.”
Dr. Chook also explores the roles of importins and exportins in diseases. In some cancers, for example, unusual amounts of one of the exportins are made, giving the cancer cells a survival advantage.
With one of her previous Welch grants, her team experimented with mutations in cargo proteins found in children with genetic disorders, including movement, autism, and other neurodevelopmental disorders. They were able to explain how these genetic mutations prevent cargoes from binding optimally to their importin, so they are defective in getting into the nucleus. She also demonstrated connections in the cargo mutations to recently discovered defects in the importin.
Working with colleagues in academia and the pharmaceutical industry, her most recent paper focuses on how a particular drug approved for multiple myeloma and a type of lymphoma interacts with an exportin. The drug blocks the exportin and can destroy it in a new way.
Her lab is making progress in understanding “degrader” drugs that target an exportin to degradation machinery. This degrader binds only to the target exportin to make a new surface that then binds to the degradation machinery.
“Welch helps so much, letting me start projects we couldn’t undertake otherwise,” Dr. Chook said.