Source 1primary paper2025MED
Toolkit/negative regulatory region (NRR)
negative regulatory region (NRR)
Also known as: NRR
Taxonomy: Mechanism Branch / Component. Workflows sit above the mechanism and technique branches rather than replacing them.
Summary
This force is generated by Epsin-mediated endocytosis of the ligand into the signal-sending cell and results in the extracellular cleavage of the force-sensing negative regulatory region (NRR) of the receptor by an ADAM10 protease on the signal-receiving cell.
Usefulness & Problems
No literature-backed usefulness or problem-fit explainer has been materialized for this record yet.
Published Workflows
Objective: Identify domains that can replace the Notch negative regulatory region as ligand-dependent, force-dependent proteolytic switches in vivo.
Why it works: The workflow places candidate domains into a Notch activation context where successful substitutes must support ligand-stimulated, force-dependent proteolysis in the developing Drosophila wing.
Epsin-mediated ligand endocytosis generates pulling forceKuzbanian/ADAM10-catalyzed extracellular cleavage activates the switchchimeric receptor-ligand engineeringin vivo screening
Stages
- 1.In vivo screen for NRR-substituting domains(broad_screen)
This stage identifies candidate domains that can replace the native force-sensing NRR in a living developmental context.
Selection: Ability of candidate domains to function as ligand-dependent proteolytic switches in place of the NRR in the developing Drosophila wing.
- 2.Mechanistic dependence assessment(confirmatory_validation)
This stage confirms that positive substitute domains operate through the same core mechanistic logic as force-dependent Notch activation rather than through an alternative activation route.
Selection: Dependence of functional substitute domains on Kuzbanian-catalyzed cleavage and Epsin-mediated ligand endocytosis.
Taxonomy & Function
Primary hierarchy
Mechanism Branch
Component: A low-level protein part used inside a larger architecture that realizes a mechanism.
Mechanisms
force-dependent extracellular proteolysisligand-dependent activationmechanosensitive proteolytic switchingPhotocleavageTarget processes
recombinationselectionInput: Chemical
Validation
Cell-freeBacteriaMammalianMouseHumanTherapeuticIndep. Replication
Observations
successMouseapplication demoDrosophila melanogaster
Inferred from claim c2 during normalization. Domains from diverse source proteins with varied sequences and predicted structures could functionally substitute for the Notch NRR in vivo. Derived from claim c2.
Source:
Supporting Sources
Ranked Claims
Domains from diverse source proteins with varied sequences and predicted structures could functionally substitute for the Notch NRR in vivo.
Chimeric Notch and DSL proteins were used in vivo in the developing Drosophila wing to screen for domains that can substitute for the Notch NRR as ligand-dependent proteolytic switches.
Approval Evidence
1 source2 linked approval claimsfirst-pass slug negative-regulatory-region-nrr
This force is generated by Epsin-mediated endocytosis of the ligand into the signal-sending cell and results in the extracellular cleavage of the force-sensing negative regulatory region (NRR) of the receptor by an ADAM10 protease on the signal-receiving cell.
Source:
functional substitutionsupports
Domains from diverse source proteins with varied sequences and predicted structures could functionally substitute for the Notch NRR in vivo.
Source:
screen resultsupports
Chimeric Notch and DSL proteins were used in vivo in the developing Drosophila wing to screen for domains that can substitute for the Notch NRR as ligand-dependent proteolytic switches.
Source:
Comparisons
No literature-backed comparison notes have been materialized for this record yet.
Ranked Citations
- 1.