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Size-dependent protein segregation creates a spatial switch for Notch and APP signaling

View ORCID ProfileMinsuk Kwak, Kaden M. Southard, Nam Hyeong Kim, Ramu Gopalappa, Woon Ryoung Kim, Minji An, Hyun Jung Lee, Justin Farlow, Anastasios Georgakopoulos, Nikolaos K. Robakis, Daeha Seo, Hyeong Bum Kim, Yong Ho Kim, View ORCID ProfileJinwoo Cheon, View ORCID ProfileZev J. Gartner, View ORCID ProfileYoung-wook Jun
doi: https://doi.org/10.1101/2020.06.28.176560
Minsuk Kwak
1Department of Otolaryngology, University of California, San Francisco, CA, USA
2Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA
3Helen Diller Family Cancer Comprehensive Center (HDFCCC), University of California, San Francisco, CA, USA
4Center for Nanomedicine, Institute for Basic Science (IBS), Seoul, Republic of Korea
5Graduate Program of Nano Biomedical Engineering (Nano BME), Advanced Science Institute, Yonsei University, Seoul, Republic of Korea
6SKKU Advanced Institute of Nanotechnology (SAINT), Sungkyunkwan University, Suwon, Republic of Korea
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  • ORCID record for Minsuk Kwak
Kaden M. Southard
1Department of Otolaryngology, University of California, San Francisco, CA, USA
2Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA
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Nam Hyeong Kim
1Department of Otolaryngology, University of California, San Francisco, CA, USA
2Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA
3Helen Diller Family Cancer Comprehensive Center (HDFCCC), University of California, San Francisco, CA, USA
6SKKU Advanced Institute of Nanotechnology (SAINT), Sungkyunkwan University, Suwon, Republic of Korea
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Ramu Gopalappa
4Center for Nanomedicine, Institute for Basic Science (IBS), Seoul, Republic of Korea
8Department of Pharmacology, Yonsei University College of Medicine, Seoul, Republic of Korea
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Woon Ryoung Kim
1Department of Otolaryngology, University of California, San Francisco, CA, USA
2Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA
3Helen Diller Family Cancer Comprehensive Center (HDFCCC), University of California, San Francisco, CA, USA
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Minji An
4Center for Nanomedicine, Institute for Basic Science (IBS), Seoul, Republic of Korea
5Graduate Program of Nano Biomedical Engineering (Nano BME), Advanced Science Institute, Yonsei University, Seoul, Republic of Korea
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Hyun Jung Lee
1Department of Otolaryngology, University of California, San Francisco, CA, USA
2Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA
3Helen Diller Family Cancer Comprehensive Center (HDFCCC), University of California, San Francisco, CA, USA
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Justin Farlow
2Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA
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Anastasios Georgakopoulos
9Department of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, USA
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Nikolaos K. Robakis
9Department of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, USA
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Daeha Seo
10Department of Emerging Materials Science, DGIST, Daegu, Republic of Korea
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Hyeong Bum Kim
4Center for Nanomedicine, Institute for Basic Science (IBS), Seoul, Republic of Korea
5Graduate Program of Nano Biomedical Engineering (Nano BME), Advanced Science Institute, Yonsei University, Seoul, Republic of Korea
8Department of Pharmacology, Yonsei University College of Medicine, Seoul, Republic of Korea
11Brain Korea 21 Plus Project, Yonsei University College of Medicine, Seoul, Republic of Korea
12Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
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Yong Ho Kim
6SKKU Advanced Institute of Nanotechnology (SAINT), Sungkyunkwan University, Suwon, Republic of Korea
7Department of Biomedical Engineering, Sungkyunkwan University, Suwon, Republic of Korea
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Jinwoo Cheon
4Center for Nanomedicine, Institute for Basic Science (IBS), Seoul, Republic of Korea
5Graduate Program of Nano Biomedical Engineering (Nano BME), Advanced Science Institute, Yonsei University, Seoul, Republic of Korea
13Department of Chemistry, Yonsei University, Seoul, Republic of Korea
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Zev J. Gartner
2Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA
14Chan Zuckerberg Biohub, University of California San Francisco, CA, USA
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  • For correspondence: zev.gartner@ucsf.edu young-wook.jun@ucsf.edu
Young-wook Jun
1Department of Otolaryngology, University of California, San Francisco, CA, USA
2Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA
3Helen Diller Family Cancer Comprehensive Center (HDFCCC), University of California, San Francisco, CA, USA
4Center for Nanomedicine, Institute for Basic Science (IBS), Seoul, Republic of Korea
5Graduate Program of Nano Biomedical Engineering (Nano BME), Advanced Science Institute, Yonsei University, Seoul, Republic of Korea
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  • ORCID record for Young-wook Jun
  • For correspondence: zev.gartner@ucsf.edu young-wook.jun@ucsf.edu
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Abstract

Aberrant cleavage of Notch and amyloid precursor proteins (APPs) by γ-secretase is implicated in numerous diseases, but how cleavage is regulated in space and time is unclear. Here, we report that cadherin-based adherens junctions (cadAJs) are sites of high cell-surface γ-secretase activity, while simultaneously excluding these γ-secretase substrates by a size-dependent mechanism, prohibiting enzyme-substrate interactions. Upon activation, Notch and APP undergo drastic spatial rearrangements to cadAJs, concentrating them with γ-secretase, wherein they are further processed for downstream signaling. Spatial mutation by decreasing (or increasing) the size of Notch extracellular domain promotes (or inhibits) signaling, respectively. Dysregulation of this spatial switch also promotes formation of more amyloidogenic Aβ. Therefore, cadAJs creates distinct biochemical compartments regulating signaling events involving γ-secretase and prevent pathogenic activation of its substrates.

Competing Interest Statement

The authors have declared no competing interest.

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Posted July 02, 2020.
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Size-dependent protein segregation creates a spatial switch for Notch and APP signaling
Minsuk Kwak, Kaden M. Southard, Nam Hyeong Kim, Ramu Gopalappa, Woon Ryoung Kim, Minji An, Hyun Jung Lee, Justin Farlow, Anastasios Georgakopoulos, Nikolaos K. Robakis, Daeha Seo, Hyeong Bum Kim, Yong Ho Kim, Jinwoo Cheon, Zev J. Gartner, Young-wook Jun
bioRxiv 2020.06.28.176560; doi: https://doi.org/10.1101/2020.06.28.176560
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Size-dependent protein segregation creates a spatial switch for Notch and APP signaling
Minsuk Kwak, Kaden M. Southard, Nam Hyeong Kim, Ramu Gopalappa, Woon Ryoung Kim, Minji An, Hyun Jung Lee, Justin Farlow, Anastasios Georgakopoulos, Nikolaos K. Robakis, Daeha Seo, Hyeong Bum Kim, Yong Ho Kim, Jinwoo Cheon, Zev J. Gartner, Young-wook Jun
bioRxiv 2020.06.28.176560; doi: https://doi.org/10.1101/2020.06.28.176560

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