7alj
From Proteopedia
Structure of Drosophila Notch EGF domains 11-13
Structural highlights
Function[NOTCH_DROME] Signaling protein, which regulates, with both positive and negative signals, the differentiation of at least central and peripheral nervous system and eye, wing disk, oogenesis, segmental appendages such as antennae and legs, and muscles, through lateral inhibition or induction. Functions as a receptor for membrane-bound ligands Delta and Serrate to regulate cell-fate determination. Upon ligand activation, and releasing from the cell membrane, the Notch intracellular domain (NICD) forms a transcriptional activator complex with Su(H) (Suppressor of hairless) and activates genes of the E(spl) complex. Essential for proper differentiation of ectoderm. Fringe (fng) acts in the Golgi to determine the type of O-linked fucose on the EGF modules in N, altering the ability of N to bind with Delta (Dl). O-fut1 also has a role in modulating the interaction. Rumi acts in the endoplasmic reticulum to glucosylate the EGF modules in N, this is required for correct folding and cleavage of N.[1] [2] Publication Abstract from PubMedAccurate Notch signalling is critical for development and homeostasis. Fine-tuning of Notch-ligand interactions has substantial impact on signalling outputs. Recent structural studies have identified a conserved N-terminal C2 domain in human Notch ligands which confers phospholipid binding in vitro. Here, we show that Drosophila ligands Delta and Serrate adopt the same C2 domain structure with analogous variations in the loop regions, including the so-called beta1-2 loop that is involved in phospholipid binding. Mutations in the beta1-2 loop of the Delta C2 domain retain Notch binding but have impaired ability to interact with phospholipids in vitro. To investigate its role in vivo, we deleted five residues within the beta1-2 loop of endogenous Delta. Strikingly, this change compromises ligand function. The modified Delta enhances phenotypes produced by Delta loss-of-function alleles and suppresses that of Notch alleles. As the modified protein is present on the cell surface in normal amounts, these results argue that C2 domain phospholipid binding is necessary for robust signalling in vivo fine-tuning the balance of trans and cis ligand-receptor interactions. The conserved C2 phospholipid-binding domain in Delta contributes to robust Notch signalling.,Martins T, Meng Y, Korona B, Suckling R, Johnson S, Handford PA, Lea SM, Bray SJ EMBO Rep. 2021 Oct 5;22(10):e52729. doi: 10.15252/embr.202152729. Epub 2021 Aug, 4. PMID:34347930[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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