RT Journal Article
SR Electronic
T1 Harnessing Notch signaling to decode mechanisms of proteolytic regulation in diverse cell-surface receptors
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 436592
DO 10.1101/436592
A1 Amanda N. Hayward
A1 Eric J. Aird
A1 Wendy R. Gordon
YR 2018
UL http://biorxiv.org/content/early/2018/10/05/436592.abstract
AB Proteolysis of transmembrane receptors is a critical cellular communication mechanism often dysregulated in disease, yet proteolytic regulation mechanisms of ~400 receptors estimated to be cleaved from the surface remain elusive due to difficulties in controlling stimulus or unknown fates of cleavage products. In Notch receptors, intercellular forces drive exposure of a cryptic protease site within a juxtamembrane “proteolytic switch” domain to activate transcriptional programs inside the cell. The facile control and readout of proteolysis in Notch has been harnessed for therapeutics and synthetic biology. Thus, we created a Synthetic Notch Assay for Proteolytic Switches (SNAPS) to screen for putative proteolytic switches that might functionally substitute for the analogous Notch domain and initiate Notch signaling. We find conformational control of cryptic protease site exposure in cell-surface receptors is not unique to Notch but is potentially common to diverse classes of receptors. We also demonstrate the assay can be used to measure proteolytic modulation by potential therapeutics.