Cryo-EM Reveals Integrin-Mediated TGF-β Activation without Release from Latent TGF-β.

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 reveal the binding interactions between the entire αvβ8 ectodomain and its intact natural ligand, L-TGF-β, as well as two different inhibitory antibody fragments to understand the structural underpinnings of αvβ8 binding specificity and TGF-β activation. Our studies reveal 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 are not required. The structural details of this mechanism provide a rational basis for therapeutic strategies to inhibit αvβ8-mediated L-TGF-β activation.

• Publication year

  2020

• Venue

  Cell

• Publication date

  2020-01-13

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.cell.2019.12.030PMID 31955848PMCID PMC7238552
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• The structural details provide a rational basis for therapeutic strategies that inhibit αvβ8-mediated latent TGF-β activation.

  Confidence 0.90

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) review
• A mechanism of αvβ8-mediated TGF-β activation is supported in which mature TGF-β signals while remaining within latent TGF-β, without requiring release and diffusion.

  Confidence 0.96

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) review
• The structural data explain the molecular basis for αvβ8 binding specificity and its role in αvβ8-mediated TGF-β activation.

  Confidence 0.94

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) review
• Cryo-electron microscopy, structure-guided mutagenesis, and cell-based assays were combined to define the binding interactions between the full αvβ8 ectodomain and intact latent TGF-β, including complexes with two inhibitory antibody fragments.

  Confidence 0.97

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) review

• cell-based assays

  assay

  Cell experiments used to assess the functional consequences of αvβ8-ligand interactions.

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) review
• cryo-electron microscopy

  method

  A structural imaging method used to visualize the αvβ8 ectodomain and its ligand complexes.

  Aliases: cryo-EM

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) review
• inhibitory antibody fragments

  antibody fragment

  Antibody fragments tested for their ability to block αvβ8 interactions in the structural studies.

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) review
• integrin αvβ8

  protein complex

  An integrin receptor ectodomain studied here as the binding partner that recognizes latent TGF-β.

  Aliases: αvβ8

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) review
• latent tgf-β

  ligand

  The intact latent form of transforming growth factor-β that serves as the ligand in this study.

  Aliases: L-TGF-β, latent transforming growth factor-β

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) review
• structure-guided mutagenesis

  method

  A protein-engineering approach that changes residues based on structural information to test interaction determinants.

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) review
• therapeutic strategies

  strategy

  Approaches intended to inhibit αvβ8-mediated latent TGF-β activation.

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) review
• αvβ8-mediated tgf-β activation

  biological process

  Activation of latent TGF-β triggered by the integrin αvβ8 receptor.

  Aliases: integrin-mediated TGF-β activation

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) review

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