Fig. 1: Proposed mechanisms of integrin-mediated L-TGF-β activation.

a, b Structural details of L-TGF-β1 latency. Superimposition of atomic models of L-TGF-β1/GARP (8VSC) with mature TGF-β1 (mTGF-β) in complex with TGF-βR1 (blue) and TGF-βR2 (green, 3KFD) reveals steric hinderance preventing binding of receptors to mature TGF-β by the lasso loop of the LAP. Two views are rotated 180°, with indicated enlarged view (circled region) in (b). GARP (gold), L-TGF-β1 monomer A (pink) or B (cyan), mTGF-β1 _A (salmon). Positioning of GARP and receptors relative to the membrane (grey) approximated based on predicted linkers lengths. c Intracellular cytoskeletal tensile force model of αvβ6-mediated L-TGF-β activation requiring the αvβ6 extended-open pose¹⁰ derived from MD simulation based on ipsilateral architecture (not domain-swapped) without GARP. Coloring convention for monomer A/B is the same as panel a, with αv (green), β-subunit blue). d Model of αvβ8-mediated L-TGF-β activation⁵. Left: αvβ8 only in extended-closed pose before, left, and after, right, binding to L-TGF-β. Note L-TGF-β is in contralateral configuration (domain-swapped) in proposed entropy redistribution model of TGF-β activation without release independent of intracellular cytoskeletal tensile force. Coloring as above. e Structures supporting entropy redistribution model⁵. Left: Cryo-EM density maps of unbound αvβ8 and L-TGF-β1. Right: selected class of αvβ8/L-TGF-β1/GARP complex, where densities of GARP and most of mature TGF-β with increased flexibility after αvβ8 binding. Coloring as above. f Proposed tensile force-induced TGF-β activation with L-TGF-β domain swapped. Left: unbound αvβ6, extended-closed, and L-TGF-β domain-swapped. Right: actin cytoskeleton tensile force transduced through extended-open β6 leg to contralateral L-TGF-β monomer. Coloring as above. Integrin cartoons created in BioRender. Nishimura, S. (2025) https://BioRender.com/29k4zvb.