9B3G

Human Notch-1 EGFs 21-23

Summary for 9B3G

• Entry DOI: 10.2210/pdb9b3g/pdb
• Descriptor: Neurogenic locus notch homolog protein 1, BARIUM ION (3 entities in total)
• Functional Keywords: notch, egf, calcium-binding, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 12805.34

Authors

Johnson, S.,Sheppard, D.,Handford, P.A.,Lea, S.M. (deposition date: 2024-03-19, release date: 2024-10-16, Last modification date: 2024-12-18)

Primary citation

Bo, Z.,Rowntree, T.,Johnson, S.,Nurmahdi, H.,Suckling, R.J.,Hill, J.,Korona, B.,Weisshuhn, P.C.,Sheppard, D.,Meng, Y.,Liang, S.,Lowe, E.D.,Lea, S.M.,Redfield, C.,Handford, P.A.
Structural and functional studies of the EGF20-27 region reveal new features of the human Notch receptor important for optimal activation.
Structure, 32:2325-2336.e5, 2024

PubMed Abstract: The Notch receptor is activated by the Delta/Serrate/Lag-2 (DSL) family of ligands. The organization of the extracellular signaling complex is unknown, although structures of Notch/ligand complexes comprising the ligand-binding region (LBR), and negative regulatory region (NRR) region, have been solved. Here, we investigate the human Notch-1 epidermal growth factor-like (EGF) 20-27 region, located between the LBR and NRR, and incorporating the Abruptex (Ax) region, associated with distinctive Drosophila phenotypes. Our analyses, using crystallography, NMR and small angle X-ray scattering (SAXS), support a rigid, elongated organization for EGF20-27 with the EGF20-21 linkage showing Ca-dependent flexibility. In functional assays, Notch-1 variants containing Ax substitutions result in reduced ligand-dependent trans-activation. When cis-JAG1 was expressed, Notch activity differences between WT and Ca-binding Ax variants were less marked than seen in the trans-activation assays alone, consistent with disruption of cis-inhibition. These data indicate the importance of Ca-stabilized structure and suggest the balance of cis- and trans-interactions explains the effects of Drosophila Ax mutations.

PubMed: 39488203
DOI: 10.1016/j.str.2024.10.012

Experimental method

X-RAY DIFFRACTION (1.55 Å)