The necdin interactome: evaluating the effects of amino acid substitutions and cell stress using proximity-dependent biotinylation (BioID) and mass spectrometry

Abstract

Prader–Willi syndrome (PWS) is a neurodevelopmental disorder caused by the loss of function of a set of imprinted genes on chromosome 15q11–15q13. One of these genes, NDN, encodes necdin, a protein that is important for neuronal differentiation and survival. Loss of Ndn in mice causes defects in the formation and function of the nervous system. Necdin is a member of the melanoma-associated antigen gene (MAGE) protein family. The functions of MAGE proteins depend highly on their interactions with other proteins, and in particular MAGE proteins interact with E3 ubiquitin ligases and deubiquitinases to form MAGE-RING E3 ligase-deubiquitinase complexes. Here, we used proximity-dependent biotin identification (BioID) and mass spectrometry (MS) to determine the network of protein–protein interactions (interactome) of the necdin protein. This process yielded novel as well as known necdin-proximate proteins that cluster into a protein network. Next, we used BioID-MS to define the interactomes of necdin proteins carrying coding variants. Variant necdin proteins had interactomes that were distinct from wildtype necdin. BioID-MS is not only a useful tool to identify protein–protein interactions, but also to analyze the effects of variants of unknown significance on the interactomes of proteins involved in genetic disease.

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Abbreviations

BioID:

Proximity-dependent biotin identification

LC–MS/MS:

Liquid chromatography–tandem mass spectrometry

MAGE:

Melanoma antigen gene

MHD:

MAGE homology domain

MS:

Mass spectrometry

PWS:

Prader–Willi syndrome

WH:

Winged helix

WT:

Wildtype

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Acknowledgements

We thank Jack Moore, Julia Heaton, Christine Walker, and Jocelyn Bischof for technical assistance. We thank Drs. Seth Berger and Ann Smith for helpful discussions about the A280P and D66N variants.

Funding

This work was supported by an operating Grant from the Canadian Institutes of Health Research (Grant no. MOP 130367) (to RW) and a Women and Children’s Health Research Institute studentship (to MRS).

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Correspondence to Rachel Wevrick.

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Sanderson, M.R., Badior, K.E., Fahlman, R.P. et al. The necdin interactome: evaluating the effects of amino acid substitutions and cell stress using proximity-dependent biotinylation (BioID) and mass spectrometry. Hum Genet (2020). https://doi.org/10.1007/s00439-020-02193-9

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