UCSF professor Yifan Cheng, PhD (center), gestures while examining a Cryo-EM sample along with associate researcher Rob Seed, PhD (left), postdoctoral scholar Mingliang Jin, PhD (bottom right), and professor Stephen Nishimura, PhD (right). Photo by Noah Berger
For years, scientists have thought that TGF-Beta, a signaling protein that holds sway over an astonishing array of cellular processes from embryonic development to cancer, could only do its work once it escaped a lasso-like “straitjacket.”
But now, using cryogenic electron microscopy (cryo-EM), a powerful technique that enables scientists to make moving three-dimensional models of molecules at atomic resolution, experts at UC San Francisco have discovered that this protein is far craftier than they thought.
It shakes and wiggles from within its straitjacket, extending a few fingers to activate a neighboring receptor despite being encased at the surface of the cell.
The findings, published on Sept. 16 in Cell, upend decades-old dogma on how TGF-Beta works. It could help scientists improve the many therapies aimed at controlling it, including an important new class of cancer therapies called checkpoint inhibitors that have worked less well than expected.
And on a more basic level, the work suggests an even wilder picture than scientists had imagined, as important players like TGF-Beta morph into unexpected shapes to accomplish the seemingly impossible in our cells.
“The field has historically focused on stabilizing these kinds of signals to get a high-resolution image, but by doing that, it has ignored how flexibility could be part of their function,” said Yifan Cheng, PhD, UCSF professor of cellular and molecular pharmacology and co-senior author of the paper. “For TGF-Beta, this flexibility plays a vital role, and we think it could explain how other poorly-understood signals work – with implications for understanding and treating disease.”
An immobilized signal manages to pass its message
Four years ago, Cheng, who is also an investigator with the Howard Hughes Medical Institute (HHMI), and co-senior author Stephen Nishimura, MD, discovered that TGF-Beta could signal to a receptor even when bound within its straitjacket, whose scientific name is latency-associated protein (LAP).