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Using proteomics to identify ubiquitin ligase–substrate pairs: how novel methods may unveil therapeutic targets for neurodegenerative diseases

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Abstract

Ubiquitin ligases play an integral role in fine-tuning signaling cascades necessary for normal cell function. Aberrant regulation of ubiquitin ligases has been implicated in several neurodegenerative diseases, generally, due to mutations within the E3 ligase itself. Several proteomic-based methods have recently emerged to facilitate the rapid identification of ligase–substrate pairs—a previously challenging feat due to the transient nature of ligase–substrate interactions. These novel methods complement standard immunoprecipitations (IPs) and include proximity-dependent biotin identification (BioID), ubiquitin ligase–substrate trapping, tandem ubiquitin-binding entities (TUBEs), and a molecular trapping unit known as the NEDDylator. The implementation of these techniques is expected to facilitate the rapid identification of novel substrates of E3 ubiquitin ligases, a process that is likely to enhance our understanding of neurodegenerative diseases and highlight novel therapeutic targets for the treatment of neurodegenerative diseases.

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Abbreviations

AD:

Alzheimer’s disease

ALS:

Amyotrophic lateral sclerosis

AP–MS:

Affinity purification–mass spectrometry

BioID:

Proximity-dependent biotin identification

CHX:

Cycloheximide

CRAPome:

Contaminant repository for affinity purification

DUBs:

Deubiquitylases

E1:

Ubiquitin-activating enzyme

E2:

Ubiquitin-conjugating enzyme

E3:

Ubiquitin ligase

FTD:

Frontotemporal dementia

His6 :

Hexahistidine

HB-NEDD8:

Histidine–biotin-tagged NEDD8

HD:

Huntington’s disease

IP:

Immunoprecipitation

IP-LC/MS:

Immunoprecipitation followed by mass spectrometry

MS:

Mass spectrometry

NiNTA:

Nickel–nitrilotriacetic acid

PD:

Parkinson’s disease

TR-TUBE:

Trypsin-resistant tandem ubiquitin-binding entities

TUBE:

Tandem ubiquitin-binding entity

UBA:

Ubiquitin-associated domain

UPS:

Ubiquitin-proteasome system

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Acknowledgements

SLR holds a Macquarie University Research Training Program Scholarship. This research was supported by Grant-in-Aid funding from the Motor Neurone Disease Research Institute of Australia (GIA1628, GIA1638, and GIA1715), National Health & Medical Research Council (APP1095215 and APP1107644), and donations made towards MND research at Macquarie University.

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  1. Roger Chung and Albert Lee are equal last authors.

Authors and Affiliations

  1. Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, 2 Technology Place, Macquarie Park, Sydney, NSW, 2109, Australia

    Stephanie L. Rayner, Marco Morsch, Bingyang Shi, Roger Chung & Albert Lee

  2. Faculty of Medicine and Health, Sydney School of Medicine, Royal North Shore Hospital, Pacific Hwy, St Leonards, Sydney, NSW, 2065, Australia

    Mark P. Molloy

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SLR, MPM, AL, and RC conceptualised the article content. SLR wrote the manuscript. MM, MPM, BS, MM, AL, and RC assisted in revising and editing the manuscript.

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Rayner, S.L., Morsch, M., Molloy, M.P. et al. Using proteomics to identify ubiquitin ligase–substrate pairs: how novel methods may unveil therapeutic targets for neurodegenerative diseases. Cell. Mol. Life Sci. 76, 2499–2510 (2019). https://doi.org/10.1007/s00018-019-03082-9

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