{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T18:29:33Z","timestamp":1787077773958,"version":"build-2736575974"},"reference-count":36,"publisher":"National Academy of Sciences","issue":"34","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R37GM45374"],"award-info":[{"award-number":["R37GM45374"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM149305"],"award-info":[{"award-number":["R35GM149305"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,8,25]]},"abstract":"<jats:p>\n                    In resting cells, STIM1, the dimeric endoplasmic reticulum (ER) Ca\n                    <jats:sup>2+<\/jats:sup>\n                    sensor that controls store-operated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    entry (SOCE), is held in a Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -bound inactive state by multiple intramolecular restraints, or brakes. Receptor-evoked release of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    from the ER causes a large conformational change in STIM1 that releases the brakes and exposes the CRAC activation domain (CAD), enabling it to bind and open store-operated Orai1 channels in the plasma membrane. We performed single-molecule F\u00f6rster resonance energy transfer (smFRET) measurements with purified STIM1 to better understand how Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release from the luminal domain of STIM1 drives the conformational changes in the cytosolic domain that underlie CAD release. We find that Ca\n                    <jats:sup>2+<\/jats:sup>\n                    removal releases the CAD from CC1\u03b11 (the \u201cCC1 clamp\u201d) without obligatory formation of the CC1 coiled-coil that has been associated with CAD release in cells. Surprisingly, the CAD rearranges dramatically during release, as the two hairpin protomers that create its characteristic V-shaped structure are spread apart. Locking the two protomers together by cysteine crosslinking prevents CAD release, suggesting that the CAD must rearrange to escape the CC1 clamp. Our data support a model in which ER depletion-induced dimerization of the luminal SAM domains drives the cytosolic domain into multiple intermediate states including a 3-helix bundle of CC1\u03b11\/2\/3, releasing the CC1 clamp and allowing the CAD to escape through a \u201cfold-out\u201d mechanism. Subsequent formation of the CC1 coiled-coil enables the CAD to revert to its original shape and extends it toward the plasma membrane to activate Orai1.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2602410123","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T17:59:27Z","timestamp":1787075967000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Structural rearrangements underlying the activation of STIM1 by ER calcium depletion"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9484-4375","authenticated-orcid":false,"given":"Ruoyi","family":"Qiu","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00f54p054","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular and Cellular Physiology, Stanford University School of Medicine","place":["Stanford"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6010-7403","authenticated-orcid":false,"given":"Richard S.","family":"Lewis","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00f54p054","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular and Cellular Physiology, Stanford University School of Medicine","place":["Stanford"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00020.2014"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2020.06.012"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-022724-105330"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-052521-013426"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2518622122"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.02.014"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1842"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2009.05.020"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M608247200"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.08.006"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-06816-8"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.610022"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms8826"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.12.030"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1208"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-020-00672-8"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1312520111"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1111\/nyas.12938"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03062-w"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.66194"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16232-6"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1118947109"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3234"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2045"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20130089"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.112238"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07065"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0702866104"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/pro.4571"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2318874121"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2024.102946"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200604014"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(09)64011-8"},{"key":"e_1_3_4_34_2","first-page":"20.1-20.17","article-title":"Computer control of microscopes using \u00b5Manager","volume":"14","author":"Edelstein A.","year":"2010","unstructured":"A. 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