MEMO1 binds iron and modulates iron homeostasis in cancer cells
- University of Saskatchewan, Canada
- Oregon Health and Science University, United States
- University of Wisconsin-Madison, United States
Abstract
Mediator of ERBB2-driven Cell Motility 1 (MEMO1) is an evolutionary conserved protein implicated in many biological processes; however, its primary molecular function remains unknown. Importantly, MEMO1 is overexpressed in many types of cancer and was shown to modulate breast cancer metastasis through altered cell motility. To better understand the function of MEMO1 in cancer cells, we analyzed genetic interactions of MEMO1 using gene essentiality data from 1028 cancer cell lines and found multiple iron-related genes exhibiting genetic relationships with MEMO1. We experimentally confirmed several interactions between MEMO1 and iron-related proteins in living cells, most notably, transferrin receptor 2 (TFR2), mitoferrin-2 (SLC25A28), and the global iron response regulator IRP1 (ACO1). These interactions indicate that cells with high MEMO1 expression levels are hypersensitive to the disruptions in iron distribution. Our data also indicate that MEMO1 is involved in ferroptosis and is linked to iron supply to mitochondria. We have found that purified MEMO1 binds iron with high affinity under redox conditions mimicking intracellular environment and solved MEMO1 structures in complex with iron and copper. Our work reveals that the iron coordination mode in MEMO1 is very similar to that of iron-containing extradiol dioxygenases, which also display a similar structural fold. We conclude that MEMO1 is an iron-binding protein that modulates iron homeostasis in cancer cells.
Data availability
Diffraction data have been deposited in PDB under the accession code s 7KQ8, 7L5C, and 7M8H. All other data generated or analysed during this study are included in the manuscript and supporting file.
Article and author information
Author details
Franco Vizeacoumar
Funding
Canadian Institutes of Health Research (PJT-178246)
- Oleg Y Dmitriev
Natural Sciences and Engineering Research Council of Canada (RGPIN-2017-06822)
- Oleg Y Dmitriev
Canada Foundation for Innovation (CFI-33364)
- Franco Vizeacoumar
Canadian Institutes of Health Research (PJT-156309)
- Franco Vizeacoumar
Saskatchewan Cancer Agency (N/A)
- Franco Vizeacoumar
University of Saskatchewan (N/A)
- Oleg Y Dmitriev
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Richard M White, Ludwig Institute for Cancer Research, University of Oxford, United Kingdom
Version history
- Received: January 21, 2023
- Preprint posted: February 28, 2023 (view preprint)
- Accepted: April 15, 2024
- Accepted Manuscript published: April 19, 2024 (version 1)
- Version of Record published: May 9, 2024 (version 2)
Copyright
© 2024, Dolgova et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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MEMO1 binds iron and modulates iron homeostasis in cancer cells
eLife 13:e86354.
https://doi.org/10.7554/eLife.86354
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