{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T19:05:56Z","timestamp":1789758356581,"version":"4.0.1"},"reference-count":47,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"38","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.science.org\/content\/page\/science-licenses-journal-article-reuse"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["2219287"],"award-info":[{"award-number":["2219287"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R35 GM136321"],"award-info":[{"award-number":["R35 GM136321"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Dean Willard Chairs funds"}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2026,9,18]]},"abstract":"<jats:p>Signal recognition particle (SRP), a universally conserved protein-targeting machine, cotranslationally recognizes signal sequences of nascent endomembrane proteins and engages the SRP receptor (SR) at the endoplasmic reticulum (ER) membrane to unload the translating ribosome. The mechanism of membrane-associated steps in this pathway remains unclear. Here, we address this question using pre\u2013steady-state and single-molecule fluorescence measurements. SR induces release of the signal sequence from SRP and detachment of the SRP guanosine triphosphatase (GTPase) domain from the ribosome. Despite the dissolution of these contacts, SR acts as a tether to stabilize SRP association with the ribosome. Guanosine 5\u2032-triphosphate (GTP) hydrolysis in the SRP-SR complex abolishes this stabilizing effect to facilitate ribosome-nascent chain complex (RNC) release from SRP. The ER membrane selectively promotes a prehandover conformation of the RNC-SRP-SR complex, in which delayed GTP hydrolysis optimizes the transition from targeting to translocation. Our findings provide a high-resolution model for key steps during cargo handover at the ER and highlight the critical role of fine-tuned GTPase activity in the SRP pathway.<\/jats:p>","DOI":"10.1126\/sciadv.aeh8258","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T18:04:04Z","timestamp":1789754644000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["GTPase cycle and ER membrane regulate cargo handover during cotranslational protein targeting"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7138-5556","authenticated-orcid":true,"given":"Ruilin","family":"Qian","sequence":"first","affiliation":[{"name":"Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3677-066X","authenticated-orcid":true,"given":"Radoslaw J.","family":"Gora","sequence":"additional","affiliation":[{"name":"Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"SangYoon","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8663-3209","authenticated-orcid":true,"given":"Jae Ho","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sowmya","family":"Chandrasekar","sequence":"additional","affiliation":[{"name":"Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1713-4287","authenticated-orcid":true,"given":"Max Feng-Yu","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0720-5426","authenticated-orcid":true,"given":"Shimon","family":"Weiss","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6526-1733","authenticated-orcid":true,"given":"Shu-ou","family":"Shan","sequence":"additional","affiliation":[{"name":"Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biophys-051013-022653"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-072711-164732"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23010281"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI92876"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-12-820308"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020008115"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(83)96057-3"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.07975"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109350"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/340482a0"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2025.169482"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M300173200"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abg0942"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200303143"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.252.5009.1171"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(03)00161-2"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.103.4.1167"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.107.1.69"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar7924"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(89)90129-3"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.adp0787"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.563239"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1988.tb03007.x"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar3607"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature19070"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abl6459"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201901001"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1802252115"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41594-019-0297-8"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10133"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200702018"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad4992"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90313-5"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90483-7"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.325001"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.10.009"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.05.024"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41594-023-00990-0"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81130-7"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-19548-5"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.91.2.545"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3435"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2013.12.055"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1021\/ar0401348"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0401690101"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0160716"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1021\/jp063483n"}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.aeh8258","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.aeh8258","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T18:05:47Z","timestamp":1789754747000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.aeh8258"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,18]]},"references-count":47,"journal-issue":{"issue":"38","published-print":{"date-parts":[[2026,9,18]]}},"alternative-id":["10.1126\/sciadv.aeh8258"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.aeh8258","relation":{},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,18]]},"assertion":[{"value":"2026-04-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-18","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eaeh8258"}}