9D20

Crystal structure of DLK1 in complex with ACVR2B

Summary for 9D20

• Entry DOI: 10.2210/pdb9d20/pdb
• Descriptor: Activin receptor type-2B, Protein delta homolog 1, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• Functional Keywords: dlk1, acvr2b, complex, signaling, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 41980.26

Authors

Ming, Q.,Antfolk, D.,Luca, V.C. (deposition date: 2024-08-08, release date: 2025-05-07, Last modification date: 2025-07-16)

Primary citation

Antfolk, D.,Ming, Q.,Manturova, A.,Goebel, E.J.,Thompson, T.B.,Luca, V.C.
Molecular mechanism of Activin receptor inhibition by DLK1.
Nat Commun, 16:5976-5976, 2025

PubMed Abstract: Delta-like non-canonical Notch ligand 1 (DLK1) influences myogenesis, adipogenesis, and other aspects of human development through a process that is largely attributed to the downregulation of Notch signaling. Here, we show that DLK1 does not bind to Notch receptors or affect ligand-mediated Notch activation, but instead engages the TGF-β superfamily member Activin receptor type 2B (ACVR2B). The crystal structure of the DLK1-ACVR2B complex reveals that DLK1 mimics the binding mode of canonical TGF-β ligands to compete for access to ACVR2B. In functional assays, DLK1 antagonizes Myostatin-ACVR2B signaling to promote myoblast differentiation, rationalizing a mechanism for the role of DLK1 in muscle development and regeneration. Crosstalk between Notch and TGF-β is mediated by interactions between the transcriptional regulators SMAD2/3 and the Notch intracellular domain (NICD), and DLK1 inhibits SMAD2/3-NICD colocalization. These findings indicate that DLK1 acts directly on ACVR2B to inhibit signaling, whereas the observed effects on Notch may be an indirect result of DLK1 interference with NICD-SMAD complex formation.

PubMed: 40593645
DOI: 10.1038/s41467-025-60634-3

Experimental method

X-RAY DIFFRACTION (2.673 Å)