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.

The following data sets were generated

Article and author information

Author details

  1. Natalia Dolgova

    Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, Canada
    Competing interests
    The authors declare that no competing interests exist.
  2. Eva-Maria E Uhlemann

    Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Michal T Boniecki

    Protein Characterization and Crystallization Facility, University of Saskatchewan, Saskatoon, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. Frederick S Vizeacoumar

    Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, Canada
    Competing interests
    The authors declare that no competing interests exist.
  5. Anjuman Ara

    Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, Canada
    Competing interests
    The authors declare that no competing interests exist.
  6. Paria Nouri

    Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, Canada
    Competing interests
    The authors declare that no competing interests exist.
  7. Martina Ralle

    Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Marco Tonelli

    National Magnetic Resonance Facility at Madison, University of Wisconsin-Madison, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Syed A Abbas

    Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, Canada
    Competing interests
    The authors declare that no competing interests exist.
  10. Jaala Patry

    Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, Canada
    Competing interests
    The authors declare that no competing interests exist.
  11. Hussain Elhasasna

    Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2810-3138
  12. Andrew Freywald

    Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, Canada
    Competing interests
    The authors declare that no competing interests exist.
  13. Franco Vizeacoumar

    Cancer Research Department, University of Saskatchewan, Saskatoon, Canada
    For correspondence
    franco.vizeacoumar@usask.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6452-5207
  14. Oleg Y Dmitriev

    Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, Canada
    For correspondence
    Oleg.Dmitriev@usask.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1307-5063

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.

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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  1. Natalia Dolgova
  2. Eva-Maria E Uhlemann
  3. Michal T Boniecki
  4. Frederick S Vizeacoumar
  5. Anjuman Ara
  6. Paria Nouri
  7. Martina Ralle
  8. Marco Tonelli
  9. Syed A Abbas
  10. Jaala Patry
  11. Hussain Elhasasna
  12. Andrew Freywald
  13. Franco Vizeacoumar
  14. Oleg Y Dmitriev
(2024)
MEMO1 binds iron and modulates iron homeostasis in cancer cells
eLife 13:e86354.
https://doi.org/10.7554/eLife.86354

Share this article

https://doi.org/10.7554/eLife.86354

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