Biophysical Society Thematic Meeting - October 13-15, 2015

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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. Suckling1 , Boguslawa Korona2, Pat Whiteman2, Penny A. Handford2 , Susan M.
Lea1.
1University of Oxford, Oxford, United Kingdom, 2University 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.