ArticleProtein science : a publication of the Protein Society2025
Cripto-1 acts as a molecular bridge linking nodal to ALK4 via distinct structural domains.
Article in Protein science : a publication of the Protein Society, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- Fatty acid synthesis promotes mtDNA release via ETS1-mediated oligomerization of VDAC1 facilitating endothelial dysfunction in sepsis-induced lung injury.Cell death and differentiation · 2025Article
- AlphaFold 3: an unprecedent opportunity for fundamental research and drug development.Precision clinical medicine · 2025Review
- Cripto-1 acts as a molecular bridge linking nodal to ALK4 via distinct structural domains.Protein science : a publication of the Protein Society · 2025Article
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7 authors.
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Abstract
The TGF-β family ligand Nodal is an essential regulator of embryonic development, orchestrating key processes such as germ layer specification and body axis formation through activation of SMAD2/3-mediated signaling. Significantly, this activation requires the co-receptor Cripto-1. However, despite their essential roles in embryogenesis, the molecular mechanism through which Cripto-1 enables Nodal to activate the SMAD2/3 pathway has remained elusive. Intriguingly, Cripto-1 also has been shown to antagonize other TGF-β family ligands, raising questions about its diverse functions. To clarify how Cripto-1 modulates TGF-β signaling, we integrated AlphaFold3 modeling, surface plasmon resonance (SPR)-based protein-protein interaction analysis, domain-specific anti-Cripto-1 antibodies, and functional studies in NTERA-2 cells. In contrast to canonical TGF-β signaling, where ligands bridge type I and type II receptors for activation, Nodal, bound to the type II receptor, utilizes Cripto-1 to recruit the type I receptor ALK4, forming a unique ternary complex for SMAD2/3 activation. Our molecular characterization of Cripto-1-mediated Nodal signaling clarifies the unique role of this enigmatic co-receptor and advances our understanding of signaling regulation within the TGF-β family. These insights have potential implications for both developmental biology and cancer research.
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