Melody Campbell, UCSF

Melody Campbell, UCSF

Special Seminar

Event Date/Location

February 19, 2020 -
4:00 pm to 5:00 pm
Schultz Laboratory 107

Speaker

  • Dr. Melody Campbell

    UCSF

Topic

Frozen But in Motion: The Structural Dynamics of Integrin-Mediated TGF-β Activation

Integrins are conformationally flexible cell surface receptors that undergo global structural rearrangements, which are thought to be linked to interactions with ligands. Integrin αvβ8 binds with exquisite specificity to latent transforming growth factor-β (L-TGF-β). This binding is essential for activating L-TGF-β presented by a variety of cell types. Inhibiting αvβ8-mediated TGF-β activation blocks immunosuppressive regulatory T-cell differentiation, which is a potential therapeutic strategy in cancer. Using cryo-electron microscopy, structure-guided mutagenesis, and cell-based assays, we define the structural details of an extended-closed conformation, identifying a stabilizing interface that forms between flexible loops that undergo a drastic restructuring upon conformational rearrangement. We also reveal the binding interactions between the αvβ8 ectodomain and its intact natural ligand, L-TGF-β to understand the structural underpinnings of αvβ8 binding specificity and TGF-β activation. Our studies uncover a mechanism of TGF-β activation where mature TGF-β signals within the confines of L-TGF-β and the release and diffusion of TGF-β is not required. The structural details of this mechanism provide a rational basis for therapeutic strategies to inhibit αvβ8-mediated L-TGF-β activation. 

Audience

Free and open to the university community and the public.

Host

Fred Hughson, Department of Molecular Biology