{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T11:25:07Z","timestamp":1784287507694,"version":"3.55.0"},"reference-count":32,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T00:00:00Z","timestamp":1697414400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Protein Science"],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Thyroglobulin must pass endoplasmic reticulum (ER) quality control to become secreted for thyroid hormone synthesis. Defective thyroglobulin, blocked in trafficking, can cause hypothyroidism. Thyroglobulin is a large protein (~2750 residues) spanning regions I\u2013II\u2013III plus a C\u2010terminal cholinesterase\u2010like domain. The cholinesterase\u2010like domain functions as an intramolecular chaperone for regions I\u2013II\u2013III, but the folding pathway leading to successful thyroglobulin trafficking remains largely unknown. Here, informed by the recent three\u2010dimensional structure of thyroglobulin as determined by cryo\u2010electron microscopy, we have bioengineered three novel classes of mutants yielding three entirely distinct quality control phenotypes. Specifically, upon expressing recombinant thyroglobulin, we find that first, mutations eliminating a disulfide bond enclosing a 200\u2010amino acid loop in region I have surprisingly little impact on the ability of thyroglobulin to fold to a secretion\u2010competent state. Next, we have identified a mutation on the surface of the cholinesterase\u2010like domain that has no discernible effect on regional folding yet affects contact between distinct regions and thereby triggers impairment in the trafficking of full\u2010length thyroglobulin. Finally, we have probed a conserved disulfide in the cholinesterase\u2010like domain that interferes dramatically with local folding, and this defect then impacts on global folding, blocking the entire thyroglobulin in the ER. These data highlight variants with distinct effects on ER quality control, inhibiting domain\u2010specific folding; folding via regional contact; neither; or both.<\/jats:p>","DOI":"10.1002\/pro.4784","type":"journal-article","created":{"date-parts":[[2023,9,17]],"date-time":"2023-09-17T18:49:53Z","timestamp":1694976593000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Structural features of thyroglobulin linked to protein trafficking"],"prefix":"10.1002","volume":"32","author":[{"given":"Cintia E.","family":"Citterio","sequence":"first","affiliation":[{"name":"Division of Metabolism, Endocrinology &amp; Diabetes, Department of Internal Medicine University of Michigan  Ann Arbor Michigan USA"},{"name":"Department of Biomedical and Pharmaceutical Sciences Chapman University  Irvine California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kookjoo","family":"Kim","sequence":"additional","affiliation":[{"name":"Departments of Anesthesiology, and Physiology and Cellular Biophysics Irving Institute for Clinical and Translational Research, Columbia University Irving Medical Center  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhavana","family":"Rajesh","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology &amp; Diabetes, Department of Internal Medicine University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Pena","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology &amp; Diabetes, Department of Internal Medicine University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver Biggs","family":"Clarke","sequence":"additional","affiliation":[{"name":"Departments of Anesthesiology, and Physiology and Cellular Biophysics Irving Institute for Clinical and Translational Research, Columbia University Irving Medical Center  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4007-8799","authenticated-orcid":false,"given":"Peter","family":"Arvan","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology &amp; Diabetes, Department of Internal Medicine University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,10,16]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40618-021-01706-1"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27693-8"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2019.05.016"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.001786"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2021.111227"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-019-0184-8"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-1995-4"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)96530-0"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2008.04.023"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2015-1090"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2010.01.042"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444904019158"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.3235"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.719047"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2016.01.007"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40543-022-00330-9"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1107\/S2059798321010056"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)98913-1"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)53477-3"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.133.3.517"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1210\/endo-100-4-1129"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.02905"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.242099"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI35164"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.281337"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M806898200"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)67056-5"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-30082-4"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0905481107"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1210\/mend.12.3.0069"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.4274\/jcrpe.galenos.2021.2020.0278"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.111641"}],"container-title":["Protein 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