20th Annual Sarkar Lecture - Uncovering Hidden Mechanisms: The Essential Role of Conformational Dynamics in TGF-β1 Activation

YOU'RE INVITED! The Molecular Medicine Trainee Committee will be hosting the 20th Annual Sarkar Lecture, which will be held in the PGCRL 2nd floor Gallery on Tuesday, May 27th, 2025 at 1pm. The Sarkar Lecture is named after Dr. Bibudhendra (Amu) Sarkar, the first basic scientist hired at SickKids who was just awarded the Order of Canada this year. This lecture celebrates Dr. Sarkar's history of mentoring and inspiring trainees. For this lecture, trainees themselves initiate the invitation and host the speaker. This year, the Molecular Medicine Trainee Committee is delighted to host Dr. Yifan Cheng. Dr. Yifan Cheng is a biophysicist and structural biologist. In 1999, he joined the laboratory of Thomas Walz to setup a cryo-EM operation at Harvard Medical School, then joined the faculty of University of California San Francisco in 2006. Pioneering works of his laboratory in cryo-EM methodology and membrane protein structural biology that facilitated the “resolution revolution” of single particle cryo-EM. He has been an HHMI Investigator since 2015. Uncovering Hidden Mechanisms: The Essential Role of Conformational Dynamics in TGF-β1 Activation While single particle cryo-EM and AI-based protein structure prediction have made high-resolution structure determination more accessible, capturing protein dynamics – especially when they are integral to function – remains a major challenge. Using avb8-mediated activation of latent TGF-β1 (L-TGF-b1) as an example, I will illustrate the critical role of conformational dynamics in protein function. TGF-b, an essential regulator of development and immune homeostasis, is expressed as a latent complex (L-TGF-b1) that is non-covalently bound to its prodomain and presented on immune cell surfaces by covalent association with GARP. Binding of integrin avb8 activates L-TGF-b1/GARP complex. While it is traditionally thought that release of mature TGF-b1 is required for signaling, our previous work demonstrated that avb8-mediated autocrine signaling can occur without TGF-b1 release from its latent complex. We now show that avb8 binding induces a dynamic allosteric shift, redistributing the flexibility within L-TGF-b1 to transiently expose the active cytokine for receptor interaction – without its physical release. This highlights the importance of conformational dynamics in protein function and the need to study protein motions to uncover mechanisms missed by static structural approaches.