Biophysical Society Thematic Meeting - October 13-15, 2015

Biophysics of Proteins at Surfaces: Assembly, Activation, Signaling

Poster Abstracts

35-POS Board 35 Structures of the N-Termini of Human Notch Ligands and Their Binding to Phospholipids. Richard J. Suckling 1 , Boguslawa Korona 2 , Pat Whiteman 2 , Penny A. Handford 2 , Susan M. Lea 1 . 1 University of Oxford, Oxford, United Kingdom, 2 University of Oxford, Oxford, United Kingdom. Notch receptors and their ligands are core components of a cell-cell signalling pathway which plays a role in metazoan development, the importance of which is illustrated by several genetic disorders associated with aberrant Notch signalling. We recently identified the calcium dependent phospholipid binding C2 domain at the N-terminus of the human ligand Jagged1 (Chillakuri et al., 2013). A recent structure of the Notch ligand DLL4 in complex with Notch1 (Luca et al., 2015), has shown that EGF12 of the Notch receptor (1-4 in mammals) interacts with a loop at the side of the C2 domain of DLL4 showing that this domain can bind to both Notch and phospholipids simultaneously. The N-terminal C2 domain is conserved across the Notch ligands, and we have recently obtained crystal structures of other Notch ligands showing that the loops within the putative lipid binding site of the C2 domains are considerably variable between ligands, presumably highlighting their differing lipid binding specificity. We are interested in further elucidating the specificity of the different Notch ligands for different lipids, and in understanding the role of this interaction in the Notch signaling pathway. Chillakuri CR, Sheppard D, Ilagan MX, Holt LR, Abbott F, Liang S, Kopan R, Handford PA, Lea SM. (2013) Structural analysis uncovers lipid-binding properties of Notch ligands. Cell Rep. 5(4):861-7. Luca VC, Jude KM, Pierce NW, Nachury MV, Fischer S, Garcia KC. (2015) Structural basis for Notch1 engagement of Delta-like 4. Science. 347 (6224):847-53.

72