Pharmacology & Chemical Biology Seminar Series
10/14/2021 - 12:00 PM-1:00 PM
“A non-canonical GRK phosphorylation barcode mediates γ-secretase activity and amyloid-β generation”

Nick Todd, Grad Student 
Thathiah Laboratory - Department of Neurobiology
Graduate Program in Molecular Pharmacology
University of Pittsburgh

G protein-coupled receptor (GPCR) kinases (GRKs) orchestrate GPCR signaling pathways by regulating distinct phosphorylation patterns and binding of the multifunctional scaffolding proteins known as β-arrestins. Our research uncovers a non-canonical role of the GRK family of kinases in mediating phosphorylation of the APH1A subunit of the γ-secretase complex, a 4-subunit protease complex with over 90 known substrates. Similar to GPCRs, we show that distinct APH1A phosphorylation patterns regulate differential binding with β-arrestin 2 and functionally, γ-secretase activity and the generation of amyloid-β (Aβ) peptides - one of the main pathological hallmarks of Alzheimer's disease.


Melanie L Hoffner
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