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PC1\/3 is synthesized as the zymogen proPC1\/3, which undergoes autocatalytic maturation in the endoplasmic reticulum (ER) before trafficking to secretory granules. However, how autocatalytic maturation licenses the ER exit of PC1\/3 remains unknown. Here, we determined the structure of an immature, catalytically inactive human proPC1\/3\n                  <jats:sup>S382A<\/jats:sup>\n                  , which exits the ER as a domain-swapped homodimer. This domain-swapped conformation allows proPC1\/3\n                  <jats:sup>S382A<\/jats:sup>\n                  to complete a conserved calcium pocket normally formed after autocatalysis and thereby become competent for ER exit. By defining this calcium pocket as a conformational checkpoint for ER export, our findings provide insights into the maturation of PC1\/3 which may apply broadly to the PCSK family. Finally, our structure provides explanations for the functional consequences of many deleterious\n                  <jats:italic>PCSK1<\/jats:italic>\n                  mutations.\n                <\/jats:p>","DOI":"10.64898\/2026.07.21.739776","type":"posted-content","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T21:10:23Z","timestamp":1784927423000},"source":"Crossref","is-referenced-by-count":0,"title":["A domain-swapped proPC1\/3 structure reveals a conformational checkpoint for ER export"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7025-5530","authenticated-orcid":false,"given":"Pankaj","family":"Kumar","sequence":"first","affiliation":[{"name":"Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"},{"name":"Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip A.","family":"Hyon","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rishi","family":"Nixon","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley V.","family":"Bullington","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ciara A.","family":"Payne","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris","family":"Lindberg","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8657-9348","authenticated-orcid":false,"given":"Daniel L.","family":"Kober","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026072714041904000_2026.07.21.739776v1.1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R113.481549"},{"key":"2026072714041904000_2026.07.21.739776v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3699"},{"key":"2026072714041904000_2026.07.21.739776v1.3","doi-asserted-by":"crossref","unstructured":"Seidah NG , Pasquato A , Andr\u00e9o U . 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