{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T10:58:04Z","timestamp":1790852284048,"version":"4.1.0"},"reference-count":60,"publisher":"Wiley","issue":"19","license":[{"start":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS123649"],"award-info":[{"award-number":["NS123649"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS136370"],"award-info":[{"award-number":["NS136370"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:p>\n                    The c607C&gt;T mutation in the\n                    <jats:italic>PACS1<\/jats:italic>\n                    gene results in an Arg203Trp substitution in the multifunctional protein PACS\u20101, and drives a syndrome characterized by intellectual disability, seizures, craniofacial dysmorphisms, and various characteristics of the autism spectrum. On the molecular level, this syndrome, in part, results from enhanced association of PACS\u20101 with the protein deacetylase HDAC6. PACS\u20101 uses its Furin binding region (FBR: amino acids 101\u2013273) to directly interact with the catalytic domains of HDAC6. We present the solution structure of a chimeric PACS\u20101 FBR and use NMR to demonstrate that the PACS\u20101\/HDAC6 interaction is regulated by an intramolecular mechanism involving the central unstructured region of PACS\u20101 folding back across the FBR and engaging in contacts with an extended, positively charged loop. The R203W substitution, located in this loop, disrupts this regulatory interaction and,\n                    <jats:italic>in vitro<\/jats:italic>\n                    , displays the ability to promote aberrant protein\u2013protein interactions.\n                  <\/jats:p>","DOI":"10.1111\/febs.70492","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T07:11:51Z","timestamp":1773990711000},"page":"5717-5734","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The\n                    <scp>R203W<\/scp>\n                    substitution drives\n                    <scp>PACS<\/scp>\n                    \u20101 syndrome by disrupting intramolecular regulation"],"prefix":"10.1111","volume":"293","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9535-1801","authenticated-orcid":false,"given":"Troy C.","family":"Krzysiak","sequence":"first","affiliation":[{"name":"Department of Structural Biology University of Pittsburgh School of Medicine  Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In\u2010Ja L.","family":"Byeon","sequence":"additional","affiliation":[{"name":"Department of Structural Biology University of Pittsburgh School of Medicine  Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Ponticelli","sequence":"additional","affiliation":[{"name":"Department of Structural Biology University of Pittsburgh School of Medicine  Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary E.","family":"Lucas","sequence":"additional","affiliation":[{"name":"Department of Structural Biology University of Pittsburgh School of Medicine  Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lariah","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Structural Biology University of Pittsburgh School of Medicine  Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"DeHaven","sequence":"additional","affiliation":[{"name":"Department of Structural Biology University of Pittsburgh School of Medicine  Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"Thomas","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics University of Pittsburgh School of Medicine  Pittsburgh PA USA"},{"name":"Hillman Cancer Center University of Pittsburgh School of Medicine  Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9072-3525","authenticated-orcid":false,"given":"Angela M.","family":"Gronenborn","sequence":"additional","affiliation":[{"name":"Department of Structural Biology University of Pittsburgh School of Medicine  Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,20]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81420-8"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.9.2191"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600885"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1590-09.2009"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20081016"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/35004038"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)01162-5"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-020-1167-x"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.10.013"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-42176-8"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00628-13"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2607"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.11.020"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12544"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12956"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.9"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61058"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1413606"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdg596"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601336"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E11-11-0928"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2018.10.007"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.598607"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1997.1253"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21093371"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.03.005"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13516"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/417455a"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdg115"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1900441116"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00175245"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00197804"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad1011"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab1061"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1090-7807(02)00014-9"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10858-013-9741-y"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/0263-7855(96)00009-4"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2021.729513"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-024-01011-0"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.4938"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btm404"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1047"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.52.11.2848"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2014.08.009"},{"key":"e_1_2_11_46_1","first-page":"629","article-title":"One hundred years of linkage disequilibrium","volume":"209","author":"Sved JA","year":"2018","journal-title":"Genetics"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23179649"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1097\/MCD.0000000000000237"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaapos.2017.12.008"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61964"},{"key":"e_1_2_11_51_1","first-page":"738","article-title":"Schuurs\u2010Hoeijmakers syndrome (PACS1 neurodevelopmental disorder): seven novel patients and a review","volume":"12","author":"Tenorio\u2010Casta\u00f1o J","year":"2021","journal-title":"Gen"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2020104888"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2303402120"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)80340-8"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.283.5406.1325"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1088877"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00197809"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.20449"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00228148"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2836(03)00928-8"},{"key":"e_1_2_11_61_1","unstructured":"Schrodinger LLC(2015)\u201cThe PyMOL molecular graphics system version 1.8.\u201d"}],"container-title":["The FEBS Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/febs.70492","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/febs.70492","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/febs.70492","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T10:18:39Z","timestamp":1790849919000},"score":1,"resource":{"primary":{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/10.1111\/febs.70492"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,20]]},"references-count":60,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["10.1111\/febs.70492"],"URL":"https:\/\/doi.org\/10.1111\/febs.70492","archive":["Portico"],"relation":{},"ISSN":["1742-464X","1742-4658"],"issn-type":[{"value":"1742-464X","type":"print"},{"value":"1742-4658","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,20]]},"assertion":[{"value":"2025-11-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}