Role of redox-sensitive catalytic interaction with ADAM10 in mutant-selective extracellular shedding of prion protein
Yejin Shin,
Kang-Sug Jo,
Minseok Shin,
Duri Lee,
Hyejin Yeo,
Youngsup Song,
Sang-Wook Kang
Affiliations
Yejin Shin
Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea; Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, Seoul, Republic of Korea
Kang-Sug Jo
Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea; Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, Seoul, Republic of Korea
Minseok Shin
Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea; Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, Seoul, Republic of Korea
Duri Lee
Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea; Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, Seoul, Republic of Korea
Hyejin Yeo
Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea; Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, Seoul, Republic of Korea
Youngsup Song
Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea; Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, Seoul, Republic of Korea; Asan Institute of Life Sciences, Asan Medical Center, Seoul, Republic of Korea
Sang-Wook Kang
Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea; Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, Seoul, Republic of Korea; Asan Institute of Life Sciences, Asan Medical Center, Seoul, Republic of Korea; Corresponding author. Department of Biomedical Sciences, University of Ulsan College of Medicine, 88, Olympic-ro 43gil, Songpa-gu, Seoul, 05505, Republic of Korea.
Misfolded glycosylphosphatidylinositol-anchored prion protein (PrP) is primarily degraded in lysosomes but is often rapidly removed from the cell surface before endocytosis in a preemptive manner. However, this mechanism is poorly understood. In this study, we discovered a disease-causing prion mutation (Q212P) that exceptionally promoted the extracellular release of PrP. Spatiotemporal analyses combined with genome editing identified the role of sheddase ADAM10 in Q212P shedding from the cell surface. ADAM10 was observed to catalytically interacts with Q212P but non-catalytically with wild-type PrP (wtPrP). This intrinsic difference in the interaction of ADAM10 between Q212P and wtPrP allowed Q212P to selectively access the sheddase activity of ADAM10 in a redox-sensitive manner. In addition, redox perturbation instigated the latent misfolding propensity of Q212P and disrupted the catalytic interaction between PrP and ADAM10, resulting in the accumulation of misfolded PrP on the cell surface. Upon recovery, active ADAM10 was able to reversibly release the surface Q212P. However, it might prove detrimental if unregulated resulting in unexpected proteotoxicity. This study provides a molecular basis of the mutant-selective shedding of PrP by demonstrating the catalytic interaction of ADAM10 with Q212P.
