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Insights into autoregulation of Notch 3 from Structural and Functional Studies of its negative Regulatory Region

Xu, Xiang, Choi, Sung Hee, Hu, Tiancen, Aster, Jon, Chopra, Rajiv, Fryer, Christy and Blacklow, Stephen (2015) Insights into autoregulation of Notch 3 from Structural and Functional Studies of its negative Regulatory Region. tbd.


Abstract: Notch receptors are transmembrane proteins that undergo activating proteolysis in response to stimulation by Delta- and Serrate-family ligands. A negative regulatory region (NRR), which encompasses three Lin12-Notch repeats (LNRs) and a juxtamembrane heterodimerization domain that houses the ligand-dependent processing site, normally maintains the receptor in a resting state by preventing protease cleavage prior to ligand binding. We report here the X-ray structure of the NRR of human Notch3 in its autoinhibited state, and compare it with the autoinhibited structures of the analogous regions of human Notch1 and Notch2. The overall architecture of the autoinhibited conformation, in which the three LNR modules wrap around the heterodimerization domain, is preserved in the Notch3 NRR. The autoinhibited conformation of the Notch3 NRR is less stable than that of Notch1 or Notch2, and Notch3 exhibits more basal activity that either Notch1 or Notch2 in reporter assays. Disease-associated mutations L1515P and L1519P of the heterodimerization domain lead to increased ligand-independent activation of the receptor. The Notch3 NRR uses a highly conserved surface on the third LNR module to form a dimer in the asymmetric unit of the crystal, and a similar homotypic interface exists in the previously reported Notch1 and Notch2 structures. 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.

Item Type: Article
Date Deposited: 26 Apr 2016 23:45
Last Modified: 26 Apr 2016 23:45


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