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It is activated in response to a wide variety of signals, such as those conveyed by Rap1A and Ras, through a mechanism that involves its C-terminal Ras association (RA) domains (RA1 and RA2). However, the complexity and size of PLC<jats:italic>\u03b5<\/jats:italic> has hindered its structural and functional analysis. Herein, we report the 2.7 \u00c5 crystal structure of the minimal fragment of PLC<jats:italic>\u03b5<\/jats:italic> that retains basal activity. This structure includes the RA1 domain, which forms extensive interactions with other core domains. A conserved amphipathic helix in the autoregulatory X\u2013Y linker of PLC<jats:italic>\u03b5<\/jats:italic> is also revealed, which we show modulates activity in vitro and in cells. The studies provide the structural framework for the core of this critical cardiovascular enzyme that will allow for a better understanding of its regulation and roles in disease.<\/jats:p>","DOI":"10.1038\/s42003-020-01178-8","type":"journal-article","created":{"date-parts":[[2020,8,14]],"date-time":"2020-08-14T12:27:09Z","timestamp":1597408029000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Structure of phospholipase C\u03b5 reveals an integrated RA1 domain and previously unidentified regulatory elements"],"prefix":"10.1038","volume":"3","author":[{"given":"Ngango Y.","family":"Rugema","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabeth E.","family":"Garland-Kuntz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monita","family":"Sieng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaushik","family":"Muralidharan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle M.","family":"Van Camp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannah","family":"O\u2019Neill","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"Mbongo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arielle F.","family":"Selvia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea T.","family":"Marti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda","family":"Everly","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emmanda","family":"McKenzie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7501-0148","authenticated-orcid":false,"given":"Angeline M.","family":"Lyon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,8,14]]},"reference":[{"key":"1178_CR1","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1146\/annurev-physiol-030212-183750","volume":"75","author":"G Kadamur","year":"2013","unstructured":"Kadamur, G. & Ross, E. 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