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A significant amount of cellular resources are spent on maintaining the dominant 1-stearoyl-2-arachidonyl PI(4,5)P<jats:sub>2<\/jats:sub> acyl-chain composition, while less abundant and more saturated species become more prevalent in response to specific stimuli, stress or aging. Here, we report the impact of acyl-chain structure on the biophysical properties of cation-induced PI(4,5)P<jats:sub>2<\/jats:sub> nanodomains. PI(4,5)P<jats:sub>2<\/jats:sub> species with increasing levels of acyl-chain saturation cluster in progressively more ordered nanodomains, culminating in the formation of gel-like nanodomains for fully saturated species. The formation of these gel-like domains was largely abrogated in the presence of 1-stearoyl-2-arachidonyl PI(4,5)P<jats:sub>2.<\/jats:sub> This is, to the best of our knowledge, the first report of the impact of PI(4,5)P<jats:sub>2<\/jats:sub> acyl-chain composition on cation-dependent nanodomain ordering, and provides important clues to the motives behind the enrichment of PI(4,5)P<jats:sub>2<\/jats:sub> with polyunsaturated acyl-chains. We also show how Ca<jats:sup>2+<\/jats:sup>-induced PI(4,5)P<jats:sub>2<\/jats:sub> nanodomains are able to generate local negative curvature, a phenomenon likely to play a role in membrane remodeling events.<\/jats:p>","DOI":"10.1038\/s42004-021-00603-1","type":"journal-article","created":{"date-parts":[[2021,11,29]],"date-time":"2021-11-29T11:02:58Z","timestamp":1638183778000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Acyl-chain saturation regulates the order of phosphatidylinositol 4,5-bisphosphate nanodomains"],"prefix":"10.1038","volume":"4","author":[{"given":"Lu\u00eds","family":"Borges-Ara\u00fajo","sequence":"first","affiliation":[]},{"given":"Marco M.","family":"Domingues","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2454-6908","authenticated-orcid":false,"given":"Alexander","family":"Fedorov","sequence":"additional","affiliation":[]},{"given":"Nuno C.","family":"Santos","sequence":"additional","affiliation":[]},{"given":"Manuel N.","family":"Melo","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9112-265X","authenticated-orcid":false,"given":"F\u00e1bio","family":"Fernandes","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2021,11,29]]},"reference":[{"key":"603_CR1","doi-asserted-by":"publisher","first-page":"1441","DOI":"10.1042\/BST20140149","volume":"42","author":"ME Monteiro","year":"2014","unstructured":"Monteiro, M. 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