The metal cofactor zinc and interacting membranes modulate SOD1 conformation-aggregation landscape in an in vitro ALS Model

  1. Achinta Sannigrahi
  2. Sourav Chowdhury
  3. Bidisha Das
  4. Amrita Banerjee
  5. Animesh Halder
  6. Mohammed Saleem
  7. Athi N Naganathan
  8. Sanat Karmakar
  9. Krishnananda Chattopadhyay  Is a corresponding author
  1. CSIR-Indian Institute of Chemical Biology, India
  2. Harvard University, United States
  3. Jadavpur University, India
  4. National Institute of Science Education and Research (NISER), India
  5. Indian Institute of Technology Madras, India

Abstract

Aggregation of Cu-Zn superoxide dismutase (SOD1) is implicated in the motor neuron disease, ALS. Although more than 140 disease mutations of SOD1 are available, their stability or aggregation behaviors in membrane environment are not correlated with disease pathophysiology. Here, we use multiple mutational variants of SOD1 to show that the absence of Zn, and not Cu, significantly impacts membrane attachment of SOD1 through two loop regions facilitating aggregation driven by lipid induced conformational changes. These loop regions influence both the primary (through Cu intake) and the gain of function (through aggregation) of SOD1 presumably through a shared conformational landscape. Combining experimental and theoretical frameworks using representative ALS disease mutants, we develop a 'co-factor derived membrane association model' wherein mutational stress closer to the Zn (but not to the Cu) pocket is responsible for membrane association mediated toxic aggregation and survival time scale after ALS diagnosis.

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All data generated or analyzed during this study are included in the manuscript and supporting files

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Author details

  1. Achinta Sannigrahi

    Structural Biology and Bioinformatics, CSIR-Indian Institute of Chemical Biology, Kolkata, India
    Competing interests
    The authors declare that no competing interests exist.
  2. Sourav Chowdhury

    Chemistry and Chemical Biology, Harvard University, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Bidisha Das

    Structural Biology and Bioinformatics, CSIR-Indian Institute of Chemical Biology, Kolkata, India
    Competing interests
    The authors declare that no competing interests exist.
  4. Amrita Banerjee

    Structural Biology and Bioinformatics, CSIR-Indian Institute of Chemical Biology, Kolkata, India
    Competing interests
    The authors declare that no competing interests exist.
  5. Animesh Halder

    Department of Physics, Jadavpur University, Kolkata, India
    Competing interests
    The authors declare that no competing interests exist.
  6. Mohammed Saleem

    School of Biological Sciences, National Institute of Science Education and Research (NISER), Bhubaneshwar, India
    Competing interests
    The authors declare that no competing interests exist.
  7. Athi N Naganathan

    Biotechnology, Indian Institute of Technology Madras, Chennai, India
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1655-7802
  8. Sanat Karmakar

    Department of Physics, Jadavpur University, Kolkata, India
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7627-8904
  9. Krishnananda Chattopadhyay

    Structural Biology and Bioinformatics, CSIR-Indian Institute of Chemical Biology, Kolkata, India
    For correspondence
    krish@iicb.res.in
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1449-8909

Funding

University Grants Commission (Fellowship)

  • Achinta Sannigrahi

University Grants Commission (Fellowship)

  • Sourav Chowdhury

Department of Biotechnology, Ministry of Science and Technology, India (BT/PR8475/BRB/10/1248/2013)

  • Sanat Karmakar

Science and Engineering Research Board (EMR/2016/000310)

  • Krishnananda Chattopadhyay

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Hannes Neuweiler, University of Würzburg, Germany

Publication history

  1. Received: July 25, 2020
  2. Accepted: April 1, 2021
  3. Accepted Manuscript published: April 7, 2021 (version 1)
  4. Version of Record published: April 30, 2021 (version 2)

Copyright

© 2021, Sannigrahi 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. Achinta Sannigrahi
  2. Sourav Chowdhury
  3. Bidisha Das
  4. Amrita Banerjee
  5. Animesh Halder
  6. Mohammed Saleem
  7. Athi N Naganathan
  8. Sanat Karmakar
  9. Krishnananda Chattopadhyay
(2021)
The metal cofactor zinc and interacting membranes modulate SOD1 conformation-aggregation landscape in an in vitro ALS Model
eLife 10:e61453.
https://doi.org/10.7554/eLife.61453
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