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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 \u2018co-factor derived membrane association model\u2019 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.<\/jats:p>","DOI":"10.7554\/elife.61453","type":"journal-article","created":{"date-parts":[[2021,4,7]],"date-time":"2021-04-07T08:01:43Z","timestamp":1617782503000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.61453","source":"Crossref","is-referenced-by-count":38,"title":["The metal cofactor zinc and interacting membranes modulate SOD1 conformation-aggregation landscape in an in vitro ALS model"],"prefix":"10.7554","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6037-2805","authenticated-orcid":true,"given":"Achinta","family":"Sannigrahi","sequence":"first","affiliation":[{"name":"Structural Biology & Bio-Informatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sourav","family":"Chowdhury","sequence":"additional","affiliation":[{"name":"Chemistry and Chemical Biology, Harvard University, Cambridge, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bidisha","family":"Das","sequence":"additional","affiliation":[{"name":"Structural Biology & Bio-Informatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India"},{"name":"Academy of Scientific and Innovative Research (AcSIR), CSIR- Human Resource development Centre Campus, Ghaziabad, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amrita","family":"Banerjee","sequence":"additional","affiliation":[{"name":"Hiralal Mazumdar Memorial College for Women, Kolkata, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Animesh","family":"Halder","sequence":"additional","affiliation":[{"name":"Department of Physics, Jadavpur University, Kolkata, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amaresh","family":"Kumar","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, National Institute of Science Education and Research (NISER), Bhubaneswar, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Saleem","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, National Institute of Science Education and Research (NISER), Bhubaneswar, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1655-7802","authenticated-orcid":true,"given":"Athi N","family":"Naganathan","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Bhupat & Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7627-8904","authenticated-orcid":true,"given":"Sanat","family":"Karmakar","sequence":"additional","affiliation":[{"name":"Department of Physics, Jadavpur University, Kolkata, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1449-8909","authenticated-orcid":true,"given":"Krishnananda","family":"Chattopadhyay","sequence":"additional","affiliation":[{"name":"Structural Biology & Bio-Informatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India"},{"name":"Academy of Scientific and Innovative Research (AcSIR), CSIR- Human Resource development Centre Campus, Ghaziabad, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2021,4,7]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"11263","DOI":"10.1073\/pnas.0704307104","article-title":"Metal-free superoxide dismutase forms soluble oligomers under physiological conditions: a possible general mechanism for familial ALS","volume":"104","author":"Banci","year":"2007","journal-title":"PNAS"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"6980","DOI":"10.1073\/pnas.0809845106","article-title":"Structural and dynamic aspects related to oligomerization of apo SOD1 and its mutants","volume":"106","author":"Banci","year":"2009","journal-title":"PNAS"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1038\/nature09018","article-title":"Affinity gradients drive copper to cellular destinations","volume":"465","author":"Banci","year":"2010","journal-title":"Nature"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/0167-4838(92)90261-B","article-title":"Amide modes and protein conformation","volume":"1120","author":"Bandekar","year":"1992","journal-title":"Biochimica Et Biophysica Acta (BBA) - 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