TY - JOUR
T1 - Structural Analysis Uncovers Lipid-Binding Properties of Notch Ligands
AU - Chillakuri, Chandramouli R.
AU - Sheppard, Devon
AU - Ilagan, Ma Xenia G.
AU - Holt, Laurie R.
AU - Abbott, Felicity
AU - Liang, Shaoyan
AU - Kopan, Raphael
AU - Handford, Penny A.
AU - Lea, Susan M.
N1 - Funding Information:
We thank Nancy Spinner for generous access to her human Jagged-1 mutation database and the referees for their helpful comments on the manuscript. D.S. and C.R.C. were funded by Wellcome Trust grant 087928 awarded to P.A.H. and S.M.L. Work in S.M.L.’s lab is supported by a Wellcome Senior Investigator Award (100298). We thank David Staunton of the Molecular Biophysics Suite for help with Thermofluor assays.
PY - 2013/11/27
Y1 - 2013/11/27
N2 - The Notch pathway is a core cell-cell signaling system in metazoan organisms with key roles in cell-fate determination, stem cell maintenance, immune system activation, and angiogenesis. Signals are initiated by extracellular interactions of the Notch receptor with Delta/Serrate/Lag-2 (DSL) ligands, whose structure is highly conserved throughout evolution. To date, no structure or activity has been associated with the extreme N termini of the ligands, even though numerous mutations in this region of Jagged-1 ligand lead to human disease. Here, we demonstrate that the N terminus of human Jagged-1 is a C2 phospholipid recognition domain that bindsphospholipid bilayers in a calcium-dependent fashion. Furthermore, we show that this activity is shared by a member of the other class of Notch ligands, human Delta-like-1, and the evolutionary distant Drosophila Serrate. Targeted mutagenesis of Jagged-1 C2 domain residues implicated in calcium-dependent phospholipid binding leaves Notch interactions intact but can reduce Notch activation. These results reveal an important and previously unsuspected role for phospholipid recognition in control of this key signaling system
AB - The Notch pathway is a core cell-cell signaling system in metazoan organisms with key roles in cell-fate determination, stem cell maintenance, immune system activation, and angiogenesis. Signals are initiated by extracellular interactions of the Notch receptor with Delta/Serrate/Lag-2 (DSL) ligands, whose structure is highly conserved throughout evolution. To date, no structure or activity has been associated with the extreme N termini of the ligands, even though numerous mutations in this region of Jagged-1 ligand lead to human disease. Here, we demonstrate that the N terminus of human Jagged-1 is a C2 phospholipid recognition domain that bindsphospholipid bilayers in a calcium-dependent fashion. Furthermore, we show that this activity is shared by a member of the other class of Notch ligands, human Delta-like-1, and the evolutionary distant Drosophila Serrate. Targeted mutagenesis of Jagged-1 C2 domain residues implicated in calcium-dependent phospholipid binding leaves Notch interactions intact but can reduce Notch activation. These results reveal an important and previously unsuspected role for phospholipid recognition in control of this key signaling system
UR - http://www.scopus.com/inward/record.url?scp=84888422328&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2013.10.029
DO - 10.1016/j.celrep.2013.10.029
M3 - Article
C2 - 24239355
AN - SCOPUS:84888422328
SN - 2211-1247
VL - 5
SP - 861
EP - 867
JO - Cell Reports
JF - Cell Reports
IS - 4
ER -