TY - JOUR
T1 - Insights into Autoregulation of Notch3 from Structural and Functional Studies of Its Negative Regulatory Region
AU - Xu, Xiang
AU - Choi, Sung Hee
AU - Hu, Tiancen
AU - Tiyanont, Kittichoat
AU - Habets, Roger
AU - Groot, Arjan J.
AU - Vooijs, Marc
AU - Aster, Jon C.
AU - Chopra, Rajiv
AU - Fryer, Christy
AU - Blacklow, Stephen C.
PY - 2015/7/7
Y1 - 2015/7/7
N2 - Notch receptors are transmembrane proteins that undergo activating proteolysis in response to ligand stimulation. A negative regulatory region (NRR) maintains receptor quiescence by preventing protease cleavage prior to ligand binding. We report here the X-ray structure of the NRR of autoinhibited human Notch3, and compare it with the Notch1 and Notch2 NRRs. The overall architecture of the autoinhibited conformation, in which three LIN12-Notch repeat (LNR) modules wrap around a heterodimerization domain, is preserved in Notch3, but the autoinhibited conformation of the Notch3 NRR is less stable. The Notch3 NRR uses a highly conserved surface on the third LNR module to form a dimer in the crystal. Similar homotypic interfaces exist in Notch1 and Notch2. Together, these studies reveal distinguishing structural features associated with increased basal activity of Notch3, demonstrate increased ligand-independent signaling for disease-associated mutations that map to the Notch3 NRR, and identify a conserved dimerization interface present in multiple Notch receptors.
AB - Notch receptors are transmembrane proteins that undergo activating proteolysis in response to ligand stimulation. A negative regulatory region (NRR) maintains receptor quiescence by preventing protease cleavage prior to ligand binding. We report here the X-ray structure of the NRR of autoinhibited human Notch3, and compare it with the Notch1 and Notch2 NRRs. The overall architecture of the autoinhibited conformation, in which three LIN12-Notch repeat (LNR) modules wrap around a heterodimerization domain, is preserved in Notch3, but the autoinhibited conformation of the Notch3 NRR is less stable. The Notch3 NRR uses a highly conserved surface on the third LNR module to form a dimer in the crystal. Similar homotypic interfaces exist in Notch1 and Notch2. Together, these studies reveal distinguishing structural features associated with increased basal activity of Notch3, demonstrate increased ligand-independent signaling for disease-associated mutations that map to the Notch3 NRR, and identify a conserved dimerization interface present in multiple Notch receptors.
U2 - 10.1016/j.str.2015.05.001
DO - 10.1016/j.str.2015.05.001
M3 - Article
C2 - 26051713
SN - 0969-2126
VL - 23
SP - 1227
EP - 1235
JO - Structure
JF - Structure
IS - 7
ER -