Engineered extracellular receptor constructs and uses thereof

An engineered receptor polypeptide construct comprising:

• (i) an extracellular ligand binding domain having at least one ligand binding site,
• (ii) an optional flexible polypeptide linker,
• (iii) an intramolecular peptide that binds to the at least one ligand binding site in the extracellular ligand binding domain,
• (iv) a transmembrane domain comprising at least one γ-secretase cleavage site, and
• (v) an intracellular effector domain,
• wherein when the intramolecular peptide is bound to the at least one ligand binding site, the extracellular ligand binding domain is maintained in a position that sterically inhibits γ-secretase from cleaving the construct at the at least one γ-secretase cleavage site, and
• wherein, in the presence of a cognate ligand, the intramolecular peptide is displaced, thereby releasing the extracellular ligand binding domain to a conformation that permits γ-secretase to cleave the construct at the at least one γ-secretase cleavage site and the intracellular effector domain is released, thereby producing an effect in the cell in which the engineered receptor construct is expressed.