Structural Biology of Notch Signaling

  • Kelly L. Arnett
  • Tom C. M. Seegar
  • Stephen C. BlacklowEmail author


The conserved Notch signaling pathway plays a central role in development and adult tissue homeostasis. Notch signaling is initiated by binding to a transmembrane ligand. E3 ubiquitin ligase-mediated ligand endocytosis enables release of the negative regulatory region (NRR) of Notch from autoinhibition, which then allows metalloprotease cleavage within the NRR, followed by intramembrane cleavage by the γ-secretase complex. After release from the membrane, the Notch intracellular domain translocates to the nucleus to form a transcriptionally active complex and initiate transcription of Notch-responsive genes. Structural studies of Notch and Notch-associated molecules, which have advanced our understanding of each of these steps in the Notch signaling pathway, are reviewed here.


Notch DSL Receptor signaling Protein biochemistry Structural biology Regulated intramembrane proteolysis Transcription 


Note added in proof

Since this chapter was written, a structure of a JAG1-Notch1 complex was reported (V.C. Luca et al., Science 10.1126/science.aaf9739;2017), the structure of an ADAM10 ectodomain was reported (T.C.M. Seegar et al., Cell 171, 1638–1648.e7;2017), and new structures of DLL4 and JAG2 isolated ligand fragments were reported (Suckling, R.J., et al. EMBO J 36(15): 2204–2215;2017).


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Kelly L. Arnett
    • 1
    • 2
  • Tom C. M. Seegar
    • 1
    • 2
  • Stephen C. Blacklow
    • 1
    • 2
    Email author
  1. 1.Department of Biological Chemistry and Molecular PharmacologyHarvard Medical SchoolBostonUSA
  2. 2.Department of Cancer BiologyDana Farber Cancer InstituteBostonUSA

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