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TitleDynamic allostery drives autocrine and paracrine TGF-β signaling.
Journal, issue, pagesCell, Year 2024
Publish dateSep 12, 2024
AuthorsMingliang Jin / Robert I Seed / Guoqing Cai / Tiffany Shing / Li Wang / Saburo Ito / Anthony Cormier / Stephanie A Wankowicz / Jillian M Jespersen / Jody L Baron / Nicholas D Carey / Melody G Campbell / Zanlin Yu / Phu K Tang / Pilar Cossio / Weihua Wen / Jianlong Lou / James Marks / Stephen L Nishimura / Yifan Cheng /
PubMed AbstractTGF-β, essential for development and immunity, is expressed as a latent complex (L-TGF-β) non-covalently associated with its prodomain and presented on immune cell surfaces by covalent association ...TGF-β, essential for development and immunity, is expressed as a latent complex (L-TGF-β) non-covalently associated with its prodomain and presented on immune cell surfaces by covalent association with GARP. Binding to integrin αvβ8 activates L-TGF-β1/GARP. The dogma is that mature TGF-β must physically dissociate from L-TGF-β1 for signaling to occur. Our previous studies discovered that αvβ8-mediated TGF-β autocrine signaling can occur without TGF-β1 release from its latent form. Here, we show that mice engineered to express TGF-β1 that cannot release from L-TGF-β1 survive without early lethal tissue inflammation, unlike those with TGF-β1 deficiency. Combining cryogenic electron microscopy with cell-based assays, we reveal a dynamic allosteric mechanism of autocrine TGF-β1 signaling without release where αvβ8 binding redistributes the intrinsic flexibility of L-TGF-β1 to expose TGF-β1 to its receptors. Dynamic allostery explains the TGF-β3 latency/activation mechanism and why TGF-β3 functions distinctly from TGF-β1, suggesting that it broadly applies to other flexible cell surface receptor/ligand systems.
External linksCell / PubMed:39288764
MethodsEM (single particle)
Resolution2.73 - 3.9 Å
Structure data

EMDB-43489: L-TGF-b3/avb8
Method: EM (single particle) / Resolution: 2.73 Å

EMDB-43492: L-TGF-b3/GARP
Method: EM (single particle) / Resolution: 2.93 Å

EMDB-43493: L-TGF-b1/GARP
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-43494: avb8/L-TGF-b1/GARP
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-43495: avb8/L-TGF-b1/GARP focused on avb8
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-43496: avb8/L-TGF-b1/GARP focused on L-TGF-b1/GARP
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-43876: Consensus map of avb8/L-TGF-b1/GARP complex
Method: EM (single particle) / Resolution: 3.9 Å

Source
  • Homo sapiens (human)

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