{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T04:41:25Z","timestamp":1787805685286,"version":"build-2784847793"},"reference-count":75,"publisher":"National Academy of Sciences","issue":"1","license":[{"start":{"date-parts":[[2023,12,27]],"date-time":"2023-12-27T00:00:00Z","timestamp":1703635200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["U24GM129547"],"award-info":[{"award-number":["U24GM129547"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01 GM 145811 (award-id) GM137090-01"],"award-info":[{"award-number":["R01 GM 145811 (award-id) GM137090-01"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Jordan's Guardian Angels Foundation","award":["A19-3376-S007"],"award-info":[{"award-number":["A19-3376-S007"]}]},{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35 GM147525"],"award-info":[{"award-number":["R35 GM147525"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Jordan's Guardian Angels Foundaion","award":["A19-3376-S004"],"award-info":[{"award-number":["A19-3376-S004"]}]},{"DOI":"10.13039\/100014370","name":"Simons Foundation Autism Research Initiative","doi-asserted-by":"publisher","award":["#877875"],"award-info":[{"award-number":["#877875"]}],"id":[{"id":"10.13039\/100014370","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Jordan's Guardian Angels Foundation","award":["A22-2853-S007"],"award-info":[{"award-number":["A22-2853-S007"]}]},{"name":"Jordan's Guardian Angels Foundation","award":["A22-2853-S004"],"award-info":[{"award-number":["A22-2853-S004"]}]},{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["9 P41 GM103622"],"award-info":[{"award-number":["9 P41 GM103622"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000893","name":"Simons Foundation","doi-asserted-by":"publisher","award":["U24GM129547"],"award-info":[{"award-number":["U24GM129547"]}],"id":[{"id":"10.13039\/100000893","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":[[2024,1,2]]},"abstract":"<jats:p>\n                    Intrinsically disordered regions (IDR) and short linear motifs (SLiMs) play pivotal roles in the intricate signaling networks governed by phosphatases and kinases. B56\u03b4 (encoded by\n                    <jats:italic>PPP2R5D<\/jats:italic>\n                    ) is a regulatory subunit of protein phosphatase 2A (PP2A) with long IDRs that harbor a substrate-mimicking SLiM and multiple phosphorylation sites. De novo missense mutations in\n                    <jats:italic>PPP2R5D<\/jats:italic>\n                    cause intellectual disabilities (ID), macrocephaly, Parkinsonism, and a broad range of neurological symptoms. Our single-particle cryo-EM structures of the PP2A-B56\u03b4 holoenzyme reveal that the long, disordered arms at the B56\u03b4 termini fold against each other and the holoenzyme core. This architecture suppresses both the phosphatase active site and the substrate-binding protein groove, thereby stabilizing the enzyme in a closed latent form with dual autoinhibition. The resulting interface spans over 190 \u00c5 and harbors unfavorable contacts, activation phosphorylation sites, and nearly all residues with ID-associated mutations. Our studies suggest that this dynamic interface is coupled to an allosteric network responsive to phosphorylation and altered globally by mutations. Furthermore, we found that ID mutations increase the holoenzyme activity and perturb the phosphorylation rates, and the severe variants significantly increase the mitotic duration and error rates compared to the normal variant.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2310727120","type":"journal-article","created":{"date-parts":[[2023,12,27]],"date-time":"2023-12-27T13:37:18Z","timestamp":1703684238000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":11,"title":["B56\u03b4 long-disordered arms form a dynamic PP2A regulation interface coupled with global allostery and Jordan\u2019s syndrome mutations"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0514-6474","authenticated-orcid":false,"given":"Cheng-Guo","family":"Wu","sequence":"first","affiliation":[{"name":"McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin at Madison, School of Medicine and Public Health, Madison, WI 53705"},{"name":"Biophysics Program, University of Wisconsin at Madison, Madison, WI 53706"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijaya K.","family":"Balakrishnan","sequence":"additional","affiliation":[{"name":"McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin at Madison, School of Medicine and Public Health, Madison, WI 53705"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald A.","family":"Merrill","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, IA 52242"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6196-6720","authenticated-orcid":false,"given":"Pankaj S.","family":"Parihar","sequence":"additional","affiliation":[{"name":"McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin at Madison, School of Medicine and Public Health, Madison, WI 53705"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirill","family":"Konovolov","sequence":"additional","affiliation":[{"name":"Chemistry Department, University of Wisconsin at Madison, Madison, WI 53706"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Chia","family":"Chen","sequence":"additional","affiliation":[{"name":"McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin at Madison, School of Medicine and Public Health, Madison, WI 53705"},{"name":"Molecular and Cellular Pharmacology Program, University of Wisconsin at Madison, Madison, WI 53706"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8855-0565","authenticated-orcid":false,"given":"Zhen","family":"Xu","sequence":"additional","affiliation":[{"name":"Protein and Crystallography Facility, University of Iowa, Iowa City, IA 52242"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6777-1772","authenticated-orcid":false,"given":"Hui","family":"Wei","sequence":"additional","affiliation":[{"name":"The Simons Electron Microscopy Center, New York Structural Biology Center, New York, NY 10027"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramya","family":"Sundaresan","sequence":"additional","affiliation":[{"name":"McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin at Madison, School of Medicine and Public Health, Madison, WI 53705"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6214-5211","authenticated-orcid":false,"given":"Qiang","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Boston University, Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2980-3697","authenticated-orcid":false,"given":"Brian E.","family":"Wadzinski","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Vanderbilt University, Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark R.","family":"Swingle","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, AL 36688"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0200-6532","authenticated-orcid":false,"given":"Alla","family":"Musiyenko","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, AL 36688"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3438-5685","authenticated-orcid":false,"given":"Wendy K.","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8487-8571","authenticated-orcid":false,"given":"Richard E.","family":"Honkanen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, AL 36688"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7390-5116","authenticated-orcid":false,"given":"Aussie","family":"Suzuki","sequence":"additional","affiliation":[{"name":"McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin at Madison, School of Medicine and Public Health, Madison, WI 53705"},{"name":"Biophysics Program, University of Wisconsin at Madison, Madison, WI 53706"},{"name":"Molecular and Cellular Pharmacology Program, University of Wisconsin at Madison, Madison, WI 53706"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7119-9358","authenticated-orcid":false,"given":"Xuhui","family":"Huang","sequence":"additional","affiliation":[{"name":"Biophysics Program, University of Wisconsin at Madison, Madison, WI 53706"},{"name":"Chemistry Department, University of Wisconsin at Madison, Madison, WI 53706"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6175-7280","authenticated-orcid":false,"given":"Stefan","family":"Strack","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, IA 52242"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongna","family":"Xing","sequence":"additional","affiliation":[{"name":"McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin at Madison, School of Medicine and Public Health, Madison, WI 53705"},{"name":"Biophysics Program, University of Wisconsin at Madison, Madison, WI 53706"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,12,27]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10555-008-9128-9"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.3109\/10409238.2016.1143913"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0955-0674(99)00074-5"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M202992200"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi902160t"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.10.006"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature21062"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10048-015-0466-9"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI79860"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-12-0095"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2004088"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21041286"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg-2022-108713"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25943"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2020.104123"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25863"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/celldisc.2017.27"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2016.06.024"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-016-0283-4"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2016.09.006"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-015-0120-z"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2020.06.029"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2019.08.029"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2012.08547.x"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aai8669"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2016.09.010"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.122481"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201409129"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202052295"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/19.4.562"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.79736"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-26079-0"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.100908"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2017.350"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1177\/1947601912448067"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2008.279"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10555-008-9128-9"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.26.7.2832-2844.2006"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.034868"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0611532104"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1210\/me.2007-0457"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.10.035"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0709879104"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2011.95"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsb.2021.107825"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsb.2012.04.020"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.11.033"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature05351"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21105-7"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1021\/jp204407d"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.100313"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2005.05.020"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1002\/cm.20072"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.clineuro.2022.107524"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1063\/5.0150272"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.12.030"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03327-4"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsb.2018.01.001"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsb.2005.03.010"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4169"},{"key":"e_1_3_4_61_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsb.2021.107702"},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20084"},{"key":"e_1_3_4_63_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444910007493"},{"key":"e_1_3_4_64_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444909052925"},{"key":"e_1_3_4_65_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444909042073"},{"key":"e_1_3_4_66_2","doi-asserted-by":"publisher","DOI":"10.1021\/ct700301q"},{"key":"e_1_3_4_67_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.5b00255"},{"key":"e_1_3_4_68_2","doi-asserted-by":"publisher","DOI":"10.1107\/S1600576717011438"},{"key":"e_1_3_4_69_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA119.011270"},{"key":"e_1_3_4_70_2","doi-asserted-by":"crossref","unstructured":"C. Wu The structure of the PP2A-B56Delta holoenzyme mutant - E197K. Electron Microscopy Data Bank. https:\/\/www.ebi.ac.uk\/emdb\/EMD-42018. Deposited 18 September 2023.","DOI":"10.2210\/pdb8u89\/pdb"},{"key":"e_1_3_4_71_2","doi-asserted-by":"crossref","unstructured":"C. Wu The structure of the PP2A-B56Delta holoenzyme mutant - E197K. Electron Microscopy Data Bank. https:\/\/www.rcsb.org\/structure\/41837. Deposited 5 September 2023.","DOI":"10.2210\/pdb8u1x\/pdb"},{"key":"e_1_3_4_72_2","doi-asserted-by":"crossref","unstructured":"C. Wu The structure of the PP2A-B56Delta holoenzyme mutant - E197K. Protein Data Bank. https:\/\/www.rcsb.org\/structure\/8U89. Deposited 18 September 2023.","DOI":"10.2210\/pdb8u89\/pdb"},{"key":"e_1_3_4_73_2","doi-asserted-by":"crossref","unstructured":"C. Wu The structure of the PP2A-B56Delta holoenzyme mutant - E197K. Protein Data Bank. https:\/\/www.rcsb.org\/structure\/8U1X. Deposited 5 September 2023.","DOI":"10.2210\/pdb8u1x\/pdb"},{"key":"e_1_3_4_74_2","unstructured":"Z. Xu. Protein phosphatase 2A (PP2A)-B56\u03b4 holoenzyme wildtype. Small Angle Scattering Biological Data Bank. https:\/\/www.sasbdb.org\/data\/SASDTW2. Deposited 30 October 2023."},{"key":"e_1_3_4_75_2","unstructured":"Z. Xu. Protein phosphatase 2A (PP2A)-B56\u03b4 holoenzyme E198K mutant. Small Angle Scattering Biological Data Bank. https:\/\/www.sasbdb.org\/data\/SASDTX2. Deposited 30 October 2023."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2310727120","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,6]],"date-time":"2024-11-06T17:54:47Z","timestamp":1730915687000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2310727120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,27]]},"references-count":75,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2024,1,2]]}},"alternative-id":["10.1073\/pnas.2310727120"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2310727120","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,27]]},"assertion":[{"value":"2023-07-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-11-27","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-12-27","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2310727120"}}