GPCR kinases generate an APH1A phosphorylation barcode to regulate amyloid-β generation

• Published in: Cell reports (Cambridge) Vol. 40; no. 3; p. 111110
• Main Authors: Todd, Nicholas K., Huang, Yunhong, Lee, Ji Young, Doruker, Pemra, Krieger, James M., Salisbury, Ryan, MacDonald, Matthew, Bahar, Ivet, Thathiah, Amantha
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 19.07.2022
• Subjects: Alzheimer’s disease; amyloid-beta; APH1A; G protein-coupled receptor; GPCR; GPCR kinase; GRK; MD simulations; phosphorylation barcode; β-arrestin; γ-secretase; G protein-coupled receptor; APH1A; amyloid-beta; GRK; Alzheimer’s disease; β-arrestin; CP: Neuroscience; GPCR kinase; MD simulations; GPCR; phosphorylation barcode; γ-secretase
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.111110

Emerging evidence suggests that G protein-coupled receptor (GPCR) kinases (GRKs) are associated with the pathophysiology of Alzheimer’s disease (AD). However, GRKs have not been directly implicated in regulation of the amyloid-β (Aβ) pathogenic cascade in AD. Here, we determine that GRKs phosphorylate a non-canonical substrate, anterior pharynx-defective 1A (APH1A), an integral component of the γ-secretase complex. Significantly, we show that GRKs generate distinct phosphorylation barcodes in intracellular loop 2 (ICL2) and the C terminus of APH1A, which differentially regulate recruitment of the scaffolding protein β-arrestin 2 (βarr2) to APH1A and γ-secretase-mediated Aβ generation. Further molecular dynamics simulation studies reveal an interaction between the βarr2 finger loop domain and ICL2 and ICL3 of APH1A, similar to a GPCR-β-arrestin complex, which regulates γ-secretase activity. Collectively, these studies provide insight into the molecular and structural determinants of the APH1A-βarr2 interaction that critically regulate Aβ generation. [Display omitted] •GRKs differentially regulate phosphorylation of the γ-secretase complex subunit APH1A•APH1A phosphorylation barcodes differentially regulate βarr2 recruitment to APH1A•The finger loop domain of βarr2 interacts with the cytoplasmic TM core of APH1A•Differential APH1A and βarr2 conformations regulate Aβ generation GRKs phosphorylate a growing list of non-GPCR substrates to regulate GPCR-independent signaling cascades. Todd et al. show that GRKs regulate phosphorylation of the 7 TMD subunit of the γ-secretase complex APH1A, which differentially affects recruitment of the scaffolding protein βarr2 to APH1A and modulation of γ-secretase activity and Aβ generation.